Adverse Experience Reporting Requirements for Human Drug and Licensed Biological Products; Proposed Rule DEPARTMENT OF HEALTH AND HUMAN SERVICES

SUMMARY: The Food and Drug Administration (FDA) is proposing to amend

its current adverse experience reporting regulations for human drug

products and for licensed biological products to provide consistency

with the elements of FDA Form 3500A and require the use of this new

reporting form; revise certain definitions and reporting periods and

formats as recommended by the International Conference on Harmonization

of Technical Requirements for Registration of Pharmaceuticals for Human

Use (ICH) and the World Health Organization's Council for International

Organizations of Medical Sciences (CIOMS); require applicants or

manufacturers, packers, and distributors to develop written procedures

for monitoring and reporting adverse experiences; state that reports of

adverse experiences that are forwarded by FDA to the applicant or

manufacturer, packer, and distributor should not be resubmitted to the

agency; and make other revisions to the regulations to provide

uniformity in adverse experience reporting for human drug products and

licensed biological products. These changes would simplify and

facilitate the reporting of adverse experiences and would enhance

agencywide consistency in the collection of postmarketing adverse

experience data. In addition, FDA is proposing to amend the

requirements for clinical study design and conduct and the sponsor

reporting requirements in the investigational new drug application

(IND) regulations. These amendments are intended to provide more

complete and accurate information that would enable sponsors,

investigators, and FDA to determine serious toxicities of

investigational drugs more expeditiously during clinical studies.

DATES: Submit written comments by January 25, 1995. The agency proposes

that any final rule that may issue based on this proposal become

effective 30 days after its date of publication in the Federal

Register.

ADDRESSES: Submit written comments to the Dockets Management Branch

(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr.,

Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT:

Concerning human drug products: Howard P. Muller, Center for Drug

Evaluation and Research (HFD-362), Food and Drug Administration, 7500

Standish Pl., Rockville, MD 20855, 301-594-1049.

Concerning licensed biological products: Paula S. McKeever, Center

for Biologics Evaluation and Research (HFM-635), Food and Drug

Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-

1448, 301-594-3074.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of June 3, 1993 (58 FR 31596), FDA

announced the availability of a new form for reporting adverse events

and product problems with medications, devices, and other FDA-regulated

medical products. This form is available in two versions. One version

of the form (FDA Form 3500) is to be used by health professionals for

voluntary reporting; the other version of the form (FDA Form 3500A) is

to be used by applicants or manufacturers (including licensed

manufacturers of licensed biological products), and other persons

subject to mandatory reporting requirements under FDA regulations.

Under existing regulations, drug manufacturers, packers, and

distributors and applicants for new drug products and generic drug

products must report adverse events under Sec. Sec. 310.305 and 314.80

(21 CFR 310.305 and 314.80). Elsewhere in this issue of the Federal

Register, FDA is issuing a final rule establishing new Sec. 600.80.

This section makes licensed manufacturers of biological products

subject to certain reporting requirements.

The new form is part of FDA's Medical Products Reporting Program

(MedWatch) and is designed to encourage and facilitate the reporting of

adverse events and product problems for most FDA-regulated human

medical products by the entire health care community, including

manufacturers, distributors, user facilities, and health professionals.

FDA issued the new form to simplify and consolidate the reporting of

suspected adverse events and product problems with human drug products,

biologics, and medical devices, as well as the reporting of adverse

events with other FDA-regulated medical products, such as dietary

supplements. FDA has found that, under the current system, there is

some confusion about what to report to the agency and that the existing

assortment of reporting forms and systems can interfere with the

efficient reporting of suspected problems. FDA has attempted to clarify

and simplify adverse event reporting with the new form by eliminating

redundant or nonessential elements and by clarifying those areas that

have caused confusion.

FDA Form 3500A replaces current Form FDA-1639, as well as most

other adverse event and product problem reporting forms currently

required by the agency. Adverse events associated with vaccines will

continue to be reported through the FDA and Centers for Disease Control

and Prevention Vaccine Adverse Event Reporting System (VAERS). FDA is

proposing to amend the adverse experience reporting requirements for

human drug products and for licensed biological products to be

consistent with the elements of FDA Form 3500A.

In developing FDA Forms 3500 and 3500A, the agency considered

several recommendations from ICH and CIOMS. These organizations were

formed to facilitate international consideration of issues,

particularly safety issues, concerning the use of both foreign and

domestic data in the development and use of drugs and biological

products. ICH has worked to promote the harmonization of technical

requirements for the registration of pharmaceutical products among

three regions: The European Union, Japan, and the United States. ICH

has prepared a draft guideline specific to parts of this issue

entitled: ``Clinical Safety Data Management: Definitions and Standards

for Expedited Reporting.'' In the Federal Register of July 9, 1993 (58

FR 37408), FDA published this draft guideline for public comment.

Several CIOMS working groups have worked to coordinate and standardize

the international reporting of postmarketing adverse drug reactions by

pharmaceutical manufacturers to regulatory authorities. CIOMS Working

Group II has proposed an international system of standardized time

intervals, formats, and inclusion criteria in order to lessen confusion

and reduce preparation time among manufacturers and to enable them to

report postmarketing adverse experiences more rapidly, efficiently, and

effectively (Refs. 1 and 2). FDA believes that many changes recommended

by CIOMS and ICH would result in more effective reporting of serious

adverse experiences to regulatory authorities worldwide. FDA is

proposing to amend the adverse experience reporting requirements for

human drug products and licensed biological products in part to be

consistent with certain standardized definitions, procedures, and

formats proposed by these international organizations.

FDA is also proposing to amend the requirements for clinical study

design and conduct and the sponsor reporting requirements in the IND

regulations. These amendments are intended to provide more complete and

accurate information that would enable sponsors, investigators, and FDA

to determine serious toxicities of investigational drugs more

expeditiously during clinical studies. A clinical study of fialuridine

(FIAU) resulted in several instances of severe liver and pancreatic

injury and five deaths, beginning in June 1993. This incident prompted

FDA to establish a task force to see whether the data available before

the study gave any suggestion of the serious toxicity that emerged, and

whether some differences in process or behavior by investigators and

sponsors might have made it possible or more likely for them to have

anticipated the toxicity in the 1993 study. The proposed IND amendments

contained in this document are largely the result of recommendations by

this task force.

II. Description of the Proposed Rule

A. Replacement of Form FDA-1639 and How to Obtain Copies of FDA Form

3500A

FDA's existing regulations at 21 CFR 20.112, 310.305, and 314.80

refer to Form FDA-1639. The agency is proposing to amend these

regulations to replace references to Form FDA-1639 with new FDA Form

3500A. This change is necessary because new FDA Form 3500A replaces

Form FDA-1639 (58 FR 31596).

The existing regulations at Secs. 310.305(d)(4) and 314.80(f)(4))

also provide an address where a person may obtain copies of Form FDA-

1639. FDA is proposing to amend these regulations to state where a

person can obtain copies of FDA Form 3500A. Ten or fewer copies of FDA

Form 3500A and a copy of the instructions for completing the form can

be obtained from the Division of Epidemiology and Surveillance (HFD-

730), Center for Drug Evaluation and Research, Food and Drug

Administration, 5600 Fishers Lane, Rockville, MD 20857. Large numbers

of copies (greater than 10 copies) may be obtained by writing to the

Consolidated Forms and Publications Distribution Center, Washington

Commerce Center, 3222 Hubbard Rd., Landover, MD 20785.

B. Definitions of ``Data Lock-Point'' and ``International Birth Date''

FDA is proposing to amend Secs. 314.80(a) and 600.80(a) to define

the terms ``data lock-point'' and ``international birth date.'' The

``data lock-point'' is the end of the reporting period (cutoff date)

for data to be incorporated into a specific postmarketing adverse

experience periodic report. On this date, the data available to the

reporter are held for review and evaluation by the applicant or

licensed manufacturer prior to being submitted to FDA. The

international birth date is the date that the first regulatory

authority in the world approved the human drug or biological product

for marketing. As explained further in section II.E. of this document,

each 6-month anniversary of the international birth date is the data

lock-point for data to be incorporated into a specific postmarketing

adverse experience periodic report.

The proposed rule would define these terms because they describe

the standardized international reporting period developed by CIOMS for

submitting postmarketing adverse experience reports. CIOMS developed

this standardized reporting period to lessen confusion and to enable

applicants and licensed manufacturers to prepare and submit similar

reports of adverse experiences to regulatory authorities. It would also

reduce preparation time among applicants and licensed manufacturers

because it eliminates varying due dates presently required for

submitting postmarketing adverse experience reports to regulatory

authorities worldwide. FDA believes the CIOMS reporting schedule, which

decreases reporting rates currently required by FDA for drug and

licensed biological products for the first 3 years of marketing from

every 3 months to every 6 months and increases it thereafter from every

12 months to every 6 months, permits adequate time for reporters to

make periodic submissions to regulatory authorities. In addition, the

agency believes that the proposed reporting frequency is sufficient to

notify FDA of potential postmarketing safety problems that do not

require expedited reporting.

C. Definition of ``Serious''

FDA's existing adverse experience reporting regulations (21 CFR

310.305(b)(4), 312.32(a), 314.80(a), and 600.80(a)) define a serious

adverse experience as one that is ``fatal or life-threatening, is

permanently disabling, requires inpatient hospitalization, or is a

congenital anomaly, cancer, or overdose.'' Consistent with new FDA Form

3500A and with recommendations by the ICH and CIOMS, the proposed rule

would amend this definition to read as follows:

Serious means an adverse drug experience occurring at any dose

that is fatal or life-threatening, results in persistent or

significant disability/incapacity, requires or prolongs inpatient

hospitalization, necessitates medical or surgical intervention to

preclude permanent impairment of a body function or permanent damage

to a body structure, or is a congenital anomaly.

The agency is proposing to remove ``cancer'' from the definition

because cancer would most often be reported under the other broader

elements in the definition. For example, cancer may be reported as

life-threatening or requiring inpatient hospitalization. Other diseases

or conditions that may be life-threatening or require hospitalization,

such as heart disease or myocardial infarction, have not been

identified as separate elements in previous definitions, and the agency

believes it is not necessary to single out cancer.

The proposed amendment would also remove ``overdose'' from the

definition of serious. Reports of overdoses that had serious outcomes

would still be reported under the other broader elements in the

definition. Reports of overdoses that did not lead to outcomes defined

as serious would provide the agency with less critical safety

information.

By adding the phrase ``occurring at any dose'' after ``adverse drug

experience'' in the definition, the agency will ensure that a serious

adverse experience at any dose, whether it is the labeled dose or a

different dose, including an overdose or an underdose, should be

reported.

FDA is also proposing to clarify the phrase ``is permanently

disabling'' by substituting ``results in persistent or significant

disability/incapacity.'' This change is intended to clarify that a

disability need not be permanent to be considered a serious adverse

experience.

The proposed amendments would also modify the phrase ``requires

inpatient hospitalization'' to read ``requires or prolongs inpatient

hospitalization.'' This change is intended to cover those situations

where a serious adverse experience occurs while the patient is already

hospitalized, and the adverse experience prolongs the patient's

hospital stay.

FDA is also proposing to add the phrase ``necessitates medical or

surgical intervention to preclude permanent impairment of a body

function or permanent damage to a body structure.'' The agency believes

such events should be considered serious adverse experiences and should

be reported. This change is also consistent with ICH's proposed

definition of a serious adverse event. FDA notes that a serious adverse

experience would not include the discontinuation of therapy, changes in

dosage, or routine treatment with a prescription medication.

D. Definitions of ``Disability'' and ``Life-Threatening''

The proposed rule would amend Secs. 310.305(b), 314.80(a), and

600.80(a) to define the terms ``disability'' and ``life-threatening.''

These terms further explain what constitutes a serious adverse

experience. ``Disability'' means a substantial disruption of one's

ability to carry out normal life functions. ``Life-threatening'' means

that the patient was, in the view of the initial reporter, at immediate

risk of death from the adverse experience as it occurred. It does not

include an adverse experience that, had it occurred in a more serious

form, might have caused death. For example, product-induced hepatitis

that resolved without evidence of hepatic failure would not be

considered life-threatening even though hepatitis of a more severe

nature can be fatal. Similarly, an allergic reaction resulting in

angioedema of the face would not be life-threatening, even though

angioedema of the larynx, allergic bronchospasm, or anaphylaxis can be

fatal. FDA believes these definitions will help enable reporters to

determine when a serious adverse experience occurs.

E. Periodic Adverse Experience Reports

Current regulations (Secs. 314.80(c)(2)(i) and 600.80(c)(2)(i))

require the submission of periodic postmarketing reports at quarterly

intervals for 3 years from the date of approval of the application, and

then annually. Quarterly reports must be submitted within 30 days of

the close of the quarter (the first quarter beginning on the date of

U.S. approval of the application); each annual report must be submitted

within 60 days of the date of U.S. approval of the application.

FDA is proposing to revise this schedule by requiring the

submission of periodic postmarketing adverse reaction reports every 6

months. The first 6-month anniversary of the international birth date

after the application is approved in the United States is the data

lock-point for the first periodic reporting term. Each subsequent 6-

month anniversary of the international birth date is the data lock-

point for subsequent periodic reporting terms for that particular

product. The proposed rule would require periodic reports to be

submitted to FDA within 45 days after the data lock-point. For example,

a product approved by FDA, or licensed, if a biological product, on

June 15, with an international birth date of April 1, would have its

first data lock-point on October 1, which is less than 6 months after

FDA approval, but which is the 6-month anniversary of the international

birth date. Therefore, the first periodic report would be for the

period of June 15 to October 1 and would be due at FDA by November 14.

The second periodic report would cover October 2 to April 1 and would

be due to the agency no later than May 15.

The proposed rule would create the same reporting schedule based on

the international birth date and data lock-point for licensed

biological product distribution reports under Sec. 600.80(c)(3).

This new reporting schedule is consistent with the standardized

international reporting period proposed by the CIOMS II Working Group.

This working group has recommended that all international regulatory

authorities accept the same reporting schedule in order to lessen

confusion and reduce preparation time by manufacturers, rather than the

current system of varying due dates. FDA believes the CIOMS reporting

schedule, which decreases reporting rates currently required by FDA for

drug and licensed biological products for the first 3 years of

marketing from every 3 months to every 6 months and increases reporting

rates thereafter from every 12 months to every 6 months, permits

adequate time for reporters to make nonexpedited submissions to

regulatory authorities. In addition, FDA believes that the proposed

reporting frequency is sufficient to alert the agency to potential

postmarketing safety problems that are not within the categories

requiring 15-day ``Alert reports.''

Applicants and licensed manufacturers who wish to submit periodic

postmarketing adverse experience reports at different intervals could,

under proposed Secs. 314.80(c)(2)(i) and 600.80(c)(2)(i), submit a

request for a waiver under 21 CFR 314.90 or 600.90 to alter the

reporting intervals for these periodic reports.

Proposed Secs. 314.80(c)(2)(i) and 600.80(c)(2)(i) would also amend

the reporting requirements for periodic postmarketing adverse

experience reports to state that, in cases where the applicant or

licensed manufacturer has received no reports of adverse experiences

during a reporting period, the applicant or licensed manufacturer

should submit a copy of the current approved labeling and a letter to

the agency in place of a periodic postmarketing adverse experience

report. The letter should identify the product, the application number,

and the reporting period, and state that no adverse experience reports

were received during that reporting period.

Sections 314.80(c)(2)(ii) and 600.80(c)(2)(ii) set forth the

contents currently required for a periodic report: (1) A narrative

summary and analysis of the information in the report and an analysis

of the 15-day postmarketing Alert reports submitted during the

reporting interval; (2) a report describing each adverse experience not

previously reported; and (3) a history of actions taken since the last

periodic report. FDA is proposing to amend these regulations to provide

a more extensive list of contents for a periodic postmarketing adverse

experience report, as follows:

1. Title Page, Table of Contents, and Introduction

This section would provide a summary of the periodic report with

page references to detailed data and information.

2. Applicant's Core Safety Data Sheet

The applicant's core safety data sheet would be a document prepared

by the applicant that contains all relevant safety information,

including adverse drug experiences, which the applicant believes should

be listed for the drug in all countries where the drug is marketed. It

may be used by the applicant as the reference document by which an

adverse drug experience is judged to be expected or unexpected for

purposes of this postmarketing periodic report. For all other

determinations of whether an adverse drug experience is expected or

unexpected, the definition in Secs. 314.80(a) or 600.80(a) would apply.

FDA recognizes that the postmarketing periodic report may be

submitted by the applicant to multiple countries and the product may

have different approved labels in the different countries. The use of

the applicant's core safety data sheet as the reference document for

determining whether an adverse drug experience is expected or not may

result in some overreporting of unexpected adverse events that actually

are expected by the U.S. approved product label. This is because the

approved label for the United States may have more safety information

included in it than the manufacturer's core safety data sheet.

An applicant may also use the approved U.S. label as the reference

by which expected and unexpected adverse drug experiences are

determined for the postmarketing periodic report. If an applicant

chooses to use the approved U.S. label for this purpose, it must

clearly be stated in this section of the report. In all instances, if

an adverse event is not listed in the U.S. label, but is in the

manufacturer's core safety data sheet, this shall be clearly noted in

the ``Overall safety evaluation'' (see section II.E.8. of this

document).

This section would also highlight clearly any changes and the

reasons for the changes in the applicant's core safety data sheet since

the previous postmarketing periodic report.

3. The Product's Marketing Status

This section would contain, in tabular form, a chronological

history of the marketing status of the product worldwide (all

regulatory and marketing decisions affecting the product) from the date

it was first approved through its current status. Approvals or

applications voluntarily withdrawn for safety reasons would have to be

included. The product would be listed by chemical (U.S. Adopted Names,

international nonproprietary names, or proper name in accordance with

``Chemical Abstracts Nomenclature Standards'') and brand name(s).

4. Regulatory Actions for Safety Reasons

This section would identify in narrative form the reasons for

significant regulatory authority or manufacturer-initiated actions

taken anywhere in the world, or to be taken imminently, for safety

reasons during the reporting period. This would include, for example,

application withdrawal or license suspension or failure to renew,

distribution restrictions, clinical trial suspension, labeling changes

due to significant safety concerns, dosage modifications, or

pharmaceutical changes.

5. Patient Exposure

This section would include the product's domestic and foreign

marketing distribution data during the reporting period. This

information would be used to calculate the extent of patient exposure.

The method used by the manufacturer to estimate patient exposure would

always be described and would include the total number of dosage units

of each dosage form and strength or potency (e.g., 100,000/5-milligram

tablets, 50,000/10-milliliter vials).

6. Individual Case Histories

These reports would be presented in line listing format with the

following 10 columns: country, source, age, gender, dose, duration of

treatment (prior to event), time to onset, description of reaction (as

reported), outcome (e.g., fatal, resolved), other comments (e.g.,

manufacturer's report number). This format is consistent with that

suggested by CIOMS. In addition, a tabular summary of the number of

adverse events by body system may be included. The individual case

reports would consist of adverse drug experiences that are: (a)

Serious, unexpected reports from published or unpublished clinical

studies where it has been concluded that there is a reasonable

possibility that the drug or licensed biological product caused the

adverse experience; (b) serious, expected or unexpected spontaneous

adverse drug experience reports and nonserious, unexpected spontaneous

adverse experience reports received directly by the applicant or

licensed manufacturer from the initial reporter or received by the

applicant or licensed manufacturer from a drug regulatory authority,

both U.S. or foreign; and (c) serious, expected or unexpected

individual published case histories and nonserious, unexpected

individual published case histories. This section would end with an

analysis by the reporter, in narrative form, of the cases submitted.

The applicant or licensed manufacturer would also attach to the end of

the postmarketing periodic report a completed FDA Form 3500A for all

U.S. spontaneous reports of adverse experiences except those not to be

included in the periodic report as specified in proposed

Secs. 314.80(c)(1)(i) and (c)(1)(ii) and 600.80(c)(1)(i) and

(c)(1)(ii), or those sent by FDA to the applicant or licensed

manufacturer.

7. Safety Studies

This section would analyze and discuss fully and critically all

toxicological, clinical, and epidemiological studies containing

important safety information.

8. Overall Safety Evaluation

This section would provide critical analysis of the safety

information provided in the periodic report as it pertains to serious

unexpected reactions, increased frequencies of known toxicity,

reactions listed in the manufacturer's core safety data sheet but not

included in the U.S. label, drug or licensed biological product

interactions, overdose, drug or licensed biological product abuse,

experiences during pregnancy or lactation, chronic treatment, pediatric

or geriatric treatment, and new safety issues. For each of these areas,

any absence of significant information would be reported. The

evaluation would indicate whether the safety profile of the product

remains consistent with cumulative experience to date and with the

previous manufacturer's core safety data sheet. The evaluation would

specify any action recommended and the reasons for such

recommendations.

9. Other Information

This section would consist of important information received after

the data lock-point. It may include significant new cases or followup

data that affect the interpretation or evaluation of existing reports.

10. FDA Form 3500A

This section would consist of a completed FDA Form 3500A for each

spontaneous U.S. adverse drug experience not reported under paragraphs

(c)(1)(i) and (c)(1)(ii) in Secs. 314.80 and 600.80.

11. Location of Adverse Experience Records

This section would identify the current address(es), including

street, city, State, and zip code, where all adverse experience reports

and records are maintained.

This revised list of contents for periodic postmarketing adverse

experience reports is generally consistent with the international

system of standardized postmarketing periodic reporting procedures and

formats proposed by the CIOMS II Working Group. This standardization

would allow applicants and licensed manufacturers to prepare a single

postmarketing periodic report of adverse experiences for regulatory

authorities worldwide. The agency also believes that the proposed rule

would improve reporting and would enhance FDA's ability to monitor

potential postmarketing safety problems.

As a result of this proposed revised list of contents for periodic

postmarketing adverse experience reports, FDA is proposing to remove

Secs. 314.80(c)(2)(iii) and 600.80(c)(2)(iii). These sections state

that periodic reporting does not apply to information obtained from

postmarketing studies, reports in the scientific literature, and

foreign marketing experience. The proposed revised list of contents

would include such information.

F. IND Amendments

FDA regulations governing the use of investigational drugs in

clinical investigations are contained in part 312 (21 CFR part 312). In

order to conduct a clinical investigation using an investigational

drug, a sponsor must first submit an IND, described in Sec. 312.23,

which contains, among other things, a description of the drug, the

results of preclinical studies intended to show that the drug can be

introduced into humans with reasonable safety, and a proposed protocol

for the investigation. This protocol provides a description of all

aspects of the study, including the identity and qualifications of the

investigators conducting the study, procedures and criteria for

selecting subjects, the amount of the drug to be administered, the

duration of use, the observations to be made to assess the effects of

the drug, and the clinical procedures, laboratory tests, and other

measures carried out to minimize risk to the patient. After the IND

becomes effective and the investigational drug is being administered to

human subjects, the sponsor is required under Sec. 312.32 to make both

telephone and written safety reports on serious and unexpected adverse

experiences associated with the administration of the drug, as well as

written reports only, on other serious adverse events associated with

administration of the drug. Under current Sec. 312.33, the sponsor is

also required to submit an annual report containing significant safety

and other information. If FDA concludes that a study would place

subjects at unreasonable and significant risk, FDA may place a study on

clinical hold. This means that the drug may not be administered to

subjects until the hold is lifted (see Sec. 312.42). FDA may also

terminate the study under Sec. 312.44 based on such safety concerns.

FDA is concerned that these IND reporting requirements may not be

adequate to protect against some unexpected adverse events. For

example, there is a potential for such events to be disguised by

patient conditions that might lead the investigator to conclude that

the experimental drug was not implicated in those events. The agency

believes that certain modifications in the way clinical investigations

are conducted and reported may help to ensure that drug toxicity is

detected as early as possible. A recent internal task force that

examined an incident that involved a fatal drug toxicity that was not

detected in early trials has recommended improvements in IND reporting

that the agency is incorporating into this proposal for public

consideration. These improvements, as explained below, are intended to

provide more frequent and more complete evaluations of potentially

serious adverse effects so that drug-related events can be detected

earlier by sponsors, investigators, and FDA.

A clinical study of a nucleoside analog, FIAU, resulted in several

instances of severe liver injury and five deaths, beginning in June

1993. The study involved 15 subjects with chronic hepatitis B virus

infection. FIAU had been considered a highly promising agent without

recognized serious toxicity. This incident prompted FDA to establish a

task force to see whether the data available prior to the study gave

any suggestion of the serious toxicity that emerged. The task force

examined data from the 1993 FIAU study as well as data from previous

studies on FIAU and a closely related drug conducted by another

sponsor. The data from these previous studies was, or should have been,

available to the sponsor of the 1993 FIAU study. The task force was

also to determine whether some differences in process or behavior by

investigators and sponsors might have made it possible or more likely

to have anticipated the toxicity. The proposed IND amendments contained

in this document are largely the result of recommendations by the task

force (Ref. 3).

Focusing on hepatic and pancreatic adverse events, the task force

reviewed the data and data analyses that were available to

investigators, sponsors, and FDA at the start of the study to determine

whether improvements in the rules governing design, analysis, and

reporting of data from clinical studies were warranted. The task force

found a number of observations and events that suggested an association

between FIAU and hepatic and/or pancreatic abnormalities. However, none

of these events was attributed by the sponsors or investigators to

FIAU. Rather, each event, even when recognized as temporally related to

a study, was attributed by investigators and sponsors to other factors,

such as concomitant drug administration and/or concurrent illness. The

task force found that an overview of the data, in which deaths and

serious adverse experiences were analyzed cumulatively, and, with the

hypothesis that the events were drug related, was not produced and thus

was not available for use by the sponsors, the principal investigators,

or FDA reviewers. Rather, the analyses performed focused on each

individual event and determined a plausible explanation, other than

drug toxicity, for each occurrence. The task force recommended that, to

detect similar patterns of events reflecting toxicity in future

studies, sponsors should conduct cumulative analyses with a systematic

consideration of the possibility that the adverse events are caused by

the investigational drug.

The proposed IND amendments would apply to all investigational

studies conducted under part 312. However, FDA invites comments from

the public and industry on whether any or all of the proposed

requirements should apply only to certain IND's, whose selection could

be determined by application of criteria that could be included in

these regulations, or only to certain phases of drug testing.

1. Clinical Study Design

FDA is proposing to amend the requirements governing IND format and

content in Sec. 312.23. Under current Sec. 312.23(a)(6), an IND must

contain the protocols for each planned study, including information

such as a statement of the study's objectives and purpose, the criteria

for patient selection and exclusion, a description of the study design,

the method for determining the dose(s) to be administered and the

duration of individual patient exposure to the drug, and a description

of clinical procedures, laboratory tests, or other measures to be taken

to monitor the effects of the drug in human subjects and to minimize

risk.

In several instances, FDA's FIAU task force found that deaths and

serious hepatic and pancreatic injuries that appear in retrospect to

have been related to FIAU were attributed by investigators and sponsors

to the subjects' underlying disease or to other drugs the subjects were

taking for their conditions. The task force made several

recommendations intended to improve the likelihood that clinical

studies will identify, early in drug development, drug toxicity that

mimics the underlying disease or the toxicity of concomitant

medications. These recommendations include: (1) Choosing study designs

and safety endpoints that increase a study's ability to distinguish

drug toxicity from underlying disease or other drug toxicity; (2)

prospectively identifying observations that will trigger certain

actions by investigators; and (3) summarizing safety data at regular

intervals with systematic considerations of the possibility that

adverse events are drug related. The proposed rule would create new

Sec. 312.23(a)(6)(iii)(h) to require that the protocols describe any

adverse clinical or laboratory outcomes in the study that are to be

immediately reported to the sponsor. These reportable events might

include death, any life-threatening event, or any other serious event

that might reflect potential drug toxicity, as suggested by preclinical

data, and include abnormal laboratory results falling outside of a

specified range. The identified events and abnormal laboratory values

are to include those that focus attention on toxicity that may target

the same organs and body systems as the underlying disease or

concomitant medications. Under the proposal, these events would be

reported to the sponsor even if they are potentially attributable to

the patient's underlying disease or concomitant medications. Proposed

Sec. 312.23(a)(6)(iii)(h) would also require instructions for

investigators, such as reporting requirements, remeasurement or

challenge procedures, or discontinuation of the drug in response to

identified events.

The task force also recommended that sponsors consider the use of a

control group (for example, placebo, active control, or historical

control) in studies that focus on safety when the underlying disease

process is likely to produce adverse events that might be confused with

drug toxicity. The task force concluded that such controls would help

detect some adverse events. Consequently, proposed

Sec. 312.23(a)(6)(iii)(i) states that sponsors should consider the use

of a formal control group when the underlying disease is likely to

produce adverse events that might be confused with drug toxicity.

The task force also recommended that sponsors attempt to estimate

the expected incidence of death and serious adverse events in the study

population that arise from the underlying disease or concomitant

medications used to treat the disease. This recommendation is reflected

in proposed new Sec. 312.23(a)(6)(iii)(j) that would require sponsors

to provide such estimates. Under the proposal, any deaths or adverse

events that exceed the estimates would create the presumption that the

events are associated with use of the investigational drug, and the

sponsor would be required to submit a written safety report to FDA.

The task force found that the followup periods in some of the FIAU

and related studies were too short to detect some of the adverse events

that occurred because significant adverse events sometimes occurred

weeks to months after dosing with FIAU ended.The task force recommended

that all protocols contained in the IND include an explicit description

of the length and type of followup to be performed so that the agency

may review the followup procedures (task force report at 57).

Accordingly, FDA is proposing to add new Sec. 312.23(a)(6)(iii)(k) to

require that the protocol section of an IND specify and justify the

length and type of followup for subjects after the conclusion of

dosing. The justification may be brief; for example, a reference to a

study of a similar drug with the same followup period. The followup

period would ensure that clinical studies are adequately designed to

detect drug toxicity that occurs after the conclusion of drug dosing.

The sponsor would propose an appropriate followup period based on

preclinical data, experience with other members of the drug class, the

drug's mechanism of action, and prior human experience. The intensity

of the followup may change with time; e.g., a full evaluation might be

scheduled for 2 weeks postdosing, with a telephone followup for

possible serious events at a later time. Ordinarily, in Phase 1 and 2

studies, telephone followup should occur at 3 months after the dosing

is completed, but alternative timeframes and procedures can be proposed

by the sponsor. For some drugs, like FIAU, a review of available data

may suggest that the minimum followup period should be longer than 3

months.

Current regulations in Sec. 312.56 require sponsors to review and

evaluate the evidence relating to a drug's safety and effectiveness as

it is obtained from investigators. The regulations also require

sponsors to report safety information to FDA. The task force observed

that in the FIAU study sponsors may not have had available adequate

resources to evaluate safety data reported by investigators. The

proposed rule would amend Sec. 312.56(c) to require sponsors, in

addition to reviewing and evaluating safety and effectiveness

information, to develop a safety monitoring and evaluation program

before starting clinical trials. This provision is intended to ensure

that sponsors have or will develop adequate resources to evaluate

safety data reported by investigators and is consistent with the task

force's recommendations (see task force report at 57). Consistent with

this proposed requirement, FDA is also proposing in new

Sec. 312.23(a)(3)(v) that an IND contain a description of any safety

monitoring and evaluation program. This description would be in

addition to the introductory statement and general investigational plan

that are required under current regulations.

2. Safety Reports

FDA is proposing several amendments to the requirements for IND

safety reports in Sec. 312.32. FDA is proposing to alter the period for

submitting written safety reports, under Sec. 312.32(c)(1)(i) and

(d)(3), from 10 working days to 15 calendar days, and for submitting

safety reports by telephone, under Sec. 312.32(c)(2), from 3 working

days to 7 calendar days. FDA is also proposing to allow telephone

safety reports to be made by facsimile transmission as well as orally

by telephone. These changes will give sponsors additional time to

gather appropriate data to help interpret the reports before submitting

these reports. FDA believes the extended time period would be

sufficient to alert the agency to potential safety problems, especially

because of the new investigational reporting requirements the agency is

proposing.

Proposed Sec. 312.32(c) would also permit sponsors to submit IND

safety reports to the agency by using FDA Form 3500A. If FDA determined

that insufficient data were submitted on FDA Form 3500A, the agency

could require additional narrative data to be submitted. As explained

elsewhere in this proposal, this amendment is consistent with the

proposal to use this form for postmarketing reporting of human drug and

licensed biological product adverse experiences.

FDA is also proposing to amend the disclaimer contained in

Sec. 312.32(e) to emphasize that safety information submitted to FDA

are not to be considered admissions of causation or liability. The

proposal would substitute the word ``part'' for ``section'' so that the

revised disclaimer would clearly apply to all safety information

submitted under part 312. Summaries of such safety information would

not constitute a statement or admission that there was a causal link

between the administration of the drug and the subsequent adverse

event.

3. Semiannual Reports

FDA is proposing to amend the periodic reporting requirements in

Sec. 312.33 by adding, in addition to the annual report, a semiannual

death and serious adverse experiences report. This change is intended

to ensure that reports of deaths and other serious adverse experiences

in all clinical studies are collected and reviewed in a timely and

comprehensive manner, and that the possibility of drug relatedness is

always considered.

Under current regulations, sponsors must report deaths and serious

and unexpected adverse experiences within 3 or 10 working days only if

the events are associated with the use of the drug. ``Associated with

the use of the drug'' is defined to mean that there is a reasonable

possibility that the experience may have been caused by the drug (see

Sec. 312.32(a)). Deaths and a summary of serious adverse experiences

that occur in a clinical trial that the sponsor concludes are not

associated with use of the drug must be reported only in an IND annual

report. The task force found that many adverse experiences occurring

during the FIAU study that appear, in retrospect, to have been drug

related were not reported in safety reports, although, at times, they

were reported in the annual report as attributable to causes other than

FIAU.

The proposed rule, therefore, would create a new ``semiannual

report'' to require, among other things, the submission of reports of

all deaths, serious adverse experiences, and study discontinuations

resulting from an adverse experience, whether expected or unexpected

and whether or not there was thought to be a possibility that the death

or adverse experience was caused by the drug. In these twice yearly

reports, sponsors would also report all deaths and serious adverse

experiences that occurred during the trial or within the prescribed

followup period. The report would include data not only from studies

conducted under the IND, but also data from all premarketing studies of

the drug conducted worldwide, with an analysis of all unexpected

deaths, serious adverse experiences, and study discontinuations thought

to be related to the study drug from foreign postmarketing clinical

trials and from foreign postmarketing spontaneous or required reporting

systems. Serious adverse events should include laboratory changes that

result in discontinuation or that are identified in the study protocol

as reportable events. Sponsors would present these data both for the 6-

month reporting interval and cumulatively, and submit an analysis of

the data. The agency would expect the analysis to conform generally to

the evaluation of deaths, serious adverse experiences, and

discontinuations in the section entitled ``Integrated Summary of Safety

Information'' in FDA's ``Guideline for the Format and Content of the

Clinical and Statistical Sections of New Drug Applications.'' FDA also

recommends that the sponsor employ, in preparing the analysis, at least

one individual who had no involvement in conducting the clinical study.

The proposal would also require a sponsor to conduct a ``worst-case''

analysis of the safety data, presuming that observed adverse events

were the result of toxicity from the investigational drug, and then

attempt to refute this presumption, with appropriate data and

evaluations (task force report at 59). The analysis should include

estimates of the rate of an analyzed event occurring spontaneously in

the population and specific analyses of cases.

The sponsor would submit the semiannual report for the 6-month

period following the day the IND goes into effect, and for each 6-month

period thereafter, until the end of the followup period specified in

the protocol. The report would be due within 60 days of the end of the

reporting period. The semiannual safety report that is due during the

same period as the annual report would be submitted with the annual

report.

The task force recommended (task force report at 59) that FDA

require the submission of all available autopsy reports and medical

reports concerning all deaths reported in these semiannual reports,

because, in at least one instance during the FIAU study, the cause of

death originally reported was not fully consistent with the autopsy and

terminal medical reports later obtained for that subject. Proposed

Sec. 312.33(b)(2) would require the submission of these reports and

would require the sponsor to clarify any inconsistencies between these

reports and the cause of death reported to FDA by the sponsor. FDA is

proposing this requirement to help ensure that reports covering deaths

submitted to the agency are complete and accurate.

Under proposed Sec. 312.33(b)(3), at the request of the sponsor, or

on its own initiative, FDA may modify certain semiannual reporting

requirements where, for example, the clinical study endpoint is

mortality or where the study is blinded and full compliance with the

reporting requirement would require breaking the blind. FDA is

proposing this provision because studies vary concerning the nature and

seriousness of the disease to be treated, the number of subjects

exposed to the drug, and the general pace at which the drug's

development proceeds.

4. Special Safety Summary

In new Sec. 312.37(a), FDA also proposes an additional mechanism to

allow the agency to obtain safety data on investigational drugs and

summaries of these data not otherwise obtained through other reporting

requirements if, and when, these data are necessary. Most

investigational drugs do not present unusual safety concerns, so that

the safety data contained in the 6-month and annual reports, as well as

the IND safety reports submitted under Sec. 312.32, would provide

adequate information to allow FDA to observe drug safety. Some drugs,

however, may raise significant safety concerns either anticipated or

unanticipated, so that more comprehensive data on events that do not

meet the definition of a serious adverse reaction as well as those that

do are needed. Events that might trigger this heightened scrutiny

include agency experience with similar drugs, animal toxicity study

results, and information derived from IND safety, annual, or semiannual

reports. As recommended by the task force (task force report at 59 and

60), the proposed regulation is drafted in general language to allow

the agency, in consultation with the sponsor, flexibility in

determining when a report should be required and what information it

should contain. This flexibility is considered necessary because the

specifics of the safety summary may vary from study to study. FDA

anticipates that the safety summary will generally not only contain the

results of the cumulative analysis of deaths and serious adverse

experiences contained in the 6-month report, but also an analysis of

related events of lesser seriousness.

Although the task force recommended that FDA require safety

summaries unless an exemption had been granted to the sponsor, FDA is

proposing to require safety summaries only for those studies or

products where the agency has determined that a specific need for them

exists. FDA would generally expect safety summaries to be submitted

within 30 days after they are requested; however, the agency recognizes

that in cases where large amounts of data are required to be summarized

and those data are not readily available or easily summarized, a longer

period of time may be necessary to prepare the summary.

5. Final Clinical Study Report

Information about FIAU risks and benefits that the sponsor might

have derived from the process of collecting and analyzing study results

was delayed or never developed because final reports were not required

for the earlier clinical studies of FIAU and FIAC (a closely related

nucleoside analog). Thus, FDA is proposing in Sec. 312.37(b) to require

sponsors to submit, when required by FDA, a final report or study

summary of a clinical study. FDA anticipates that final reports usually

will not be necessary. Instituting requirements for semiannual

reporting of deaths, serious adverse experiences, and discontinuations,

and for summarization of all safety data will largely fulfill the need

for more careful monitoring and analysis of potential drug toxicity

during drug testing. In some cases, however, it may still be valuable

to have available an analysis of the results of particular trials;

e.g., to provide data on the likely effectiveness of a drug for

purposes of weighing risks against likely benefits to study subjects.

The proposal wouldrequire final clinical study reports to be submitted

within 90 days of a request from FDA, but provides for exceptions under

extraordinary circumstances.

6. Clinical Holds

Section 312.42 currently allows FDA to delay a proposed clinical

investigation or to suspend an ongoing investigation under certain

circumstances. Under the proposal, FDA would amend Sec. 312.42 to allow

the agency to place an investigation on clinical hold if the sponsor

fails to submit a special safety summary or final clinical study

report. If the same or a closely related drug is the subject of a

concurrent investigation, conducted by the same sponsor, proposed

Sec. 312.42(b)(1)(v) would require safety summaries from all

investigations or the agency could place any of the investigations on

clinical hold. FDA believes this is appropriate because data from all

studies involving the drug or closely related drugs may help FDA

evaluate the safety of each study.

7. Termination

FDA is also proposing in Sec. 312.44(b)(1)(viii) to amend the

regulations regarding termination so that failure to submit a

semiannual report would be grounds for terminating an IND. Failure to

submit an annual report is already grounds for terminating an IND, and

FDA is aware of no reason why semiannual and annual reports should be

treated differently in this matter.

FDA considers that failure to implement an adequate safety

monitoring and evaluation program, as described in proposed 21 CFR

312.56(c), would be grounds for either a clinical hold under

Sec. 312.42 or a termination of the IND under Sec. 312.44, since

failure to have a program in place would mean that ``[h]uman subjects

are or would be exposed to an unreasonable and significant risk of

illness or injury,'' which is currently grounds for either a clinical

hold or termination.

8. Review of Ongoing Investigations

FDA is also proposing to amend Sec. 312.64(b) to require

investigators to submit safety data to sponsors necessary to allow

sponsors to comply with the other proposed safety reporting

requirements, such as the proposed semiannual report. The proposed

amendment would require the investigator to comply with safety

reporting requirements established in the protocol for the study.

Current Sec. 312.64(b) requires investigators to report adverse effects

if they may reasonably be regarded as caused by, or probably caused by,

the drug. If the adverse effects are alarming, they are to be reported

to the sponsor immediately. These provisions are being retained as

minimal requirements which must be met, even if the protocol does not

require the events to be reported.

G. Written Procedures for Monitoring Adverse Experiences

FDA is also proposing to amend Secs. 310.305(a) and 314.80(b) for

marketed human drug products and Sec. 600.80(b) for licensed biological

products to require applicants or manufacturers, packers, and

distributors to develop written procedures for the surveillance,

receipt, evaluation, and reporting of adverse experiences to FDA. This

requirement would improve postmarketing surveillance by applicants or

manufacturers and would enhance an applicant's or manufacturer's

ability to evaluate and report adverse experiences to the agency. FDA

believes that this provision would not impose a new burden on

applicants and manufacturers, because it codifies a practice that is

already customary and usual in the pharmaceutical industry for handling

adverse experiences. Based on field inspections, FDA is aware that many

manufacturers already have written procedures for the receipt,

evaluation, and reporting of adverse experiences to FDA. The agency

also notes that the current good manufacturing practice (CGMP)

regulations for finished pharmaceuticals, which apply to manufacturers

of all marketed human drug and biological products, require written

procedures describing the handling of all written and oral complaints

regarding a drug product (21 CFR 211.198).

Furthermore, the agency's ``Guideline For Postmarketing Reporting

of Adverse Drug Experiences'' (Ref. 4), which provides guidance on

adverse drug experiences reported under Secs. 310.305 and 314.80,

states (at page 17) that:

Each applicant should develop standardized, formal procedures

for the surveillance, receipt, evaluation, and reporting of ADE's to

FDA. * * * All applicants should develop procedures that allow

expedited adverse experience report handling, and the applicant

should keep on file documentation of due diligence.

Elsewhere in this issue of the Federal Register FDA is announcing

the availability of a guideline entitled ``Guideline for Adverse

Experience Reporting for Licensed Biological Products.'' This guideline

discusses the reports required by Sec. 600.80 and provides guidance

concerning appropriate means of meeting the reporting requirements.

H. Resubmission of Reports Received From FDA

Under the MedWatch program, FDA will transmit reports of

spontaneously reported serious adverse experiences received by the

agency to the applicant, manufacturer, packer, or distributor (as

appropriate) on an expedited basis. Consequently, FDA is proposing to

revise Secs. 310.305(c), 314.80(b), and 600.80(b) to state that

applicants or manufacturers, packers, and distributors should not

resubmit to the agency reports of adverse experiences that the agency

has forwarded to them. In addition, FDA is proposing to revise

Secs. 314.80(c)(1)(i) and 600.80(c)(1)(i) to remove the phrase

``regardless of source'' from the description of which adverse

experiences are reported to FDA. These revisions are intended to reduce

duplicate reporting of adverse experiences to the agency, consistent

with the reporting instructions in new FDA Form 3500A. FDA notes,

however, that applicants or manufacturers, packers, and distributors

receiving reports forwarded to them by FDA are required to handle these

reports as they would any others and that followup, if obtained, is to

be sent to the agency as specified in the regulation. These followup

reports should be included, where appropriate, in the postmarketing

adverse experience periodic report.

FDA is also proposing that applicants and licensed manufacturers

incorporate into any safety analysis (i.e., periodic reports, increased

frequency reports) the expedited reports received from FDA, whether or

not additional followup information was obtained, and any information

received through Freedom of Information requests.

I. Other Revisions to the Reporting Requirements

FDA is proposing to remove Secs. 314.80(c)(2)(iii) and

600.80(c)(2)(iii). These paragraphs state that periodic reporting for

non-15-day Alert reports does not apply to adverse drug experience

information obtained from postmarketing studies and reports in the

scientific literature and from foreign marketing experience. FDA is

proposing to remove these paragraphs because this information would now

be required under the proposed revisions to the contents of a periodic

report.

Current regulations, at Sec. 314.80(c)(1)(ii), require applicants

and, at Sec. 600,80(c)(1)ii), licensed manufacturers to ``review

periodically (at least as often as the periodic reporting cycle)'' the

frequency of reports of adverse experiences and report any significant

increase in frequency to FDA. Similarly, current Sec. 310.305(c)(4)

requires manufacturers, packers,and distributors to ``review

periodically (at least once each year)'' the frequency of reports of

adverse experiences and report any significant increase in frequency to

FDA. In order to provide consistency with the proposed semiannual

reporting requirements for periodic adverse experience reports under

Secs. 314.80 and 600.80, FDA is proposing to amend Sec. 310.305 to

require manufacturers, packers, and distributors to review

periodically, at least twice each year, the frequency of adverse

experience reports for the purposes of making increased frequency

reports to FDA.

FDA is also proposing to amend Secs. 310.305(c) and 314.80(c) by

reorganizing, renumbering, and retitling the paragraphs in these

sections to distinguish between postmarketing 15-day Alert reports,

followups to postmarketing 15-day Alert reports, and increased

frequency reports. The proposed amendments would also distinguish

between the reporting intervals for postmarketing 15-day Alert reports

and the revised intervals proposed for postmarketing periodic reports.

FDA is also proposing to amend Secs. 310.305(c)(1) through (c)(4)

and 314.80(c)(1)(i), through (c)(1)(iv) to alter the period for

submitting postmarketing ``15-day'' Alert reports from 15 working days

to 15 calendar days. This change should decrease misunderstandings with

the reporting requirements as all timeframes would now be stated in

terms of calendar days. In addition, this change would increase

consistency between the premarketing and postmarketing reporting

requirements.

FDA is also proposing to amend Secs. 310.305(c)(2),

314.80(c)(1)(ii), and 600.80(c)(1)(ii) to require applicants or

manufacturers, packers, and distributors who have been unable to obtain

additional information about adverse experiences that are the subject

of postmarketing 15-day Alert reports to maintain records of their

attempts to seek additional information. These proposed revisions will

help ensure that applicants or manufacturers are making good faith

efforts to investigate adverse experiences that are the subject of

postmarketing 15-day Alert reports.

Finally, FDA is proposing to amend Secs. 310.305(d)(3)(ii) and

314.80(f)(3)(ii) to instruct applicants or manufacturers, packers, and

distributors that, before using an alternative reporting form instead

of FDA Form 3500A, they must obtain approval from MedWatch: The FDA

Medical Products Reporting Program, 5600 Fishers Lane, Rockville, MD

20852-9787. Current regulations require prior approval from the

Division of Epidemiology and Surveillance for human drug products.

J. Distribution Reports

As stated earlier, the proposed rule would change the reporting

interval for licensed biological product distribution reports to be

consistent with the suggested CIOMS standardized reporting period for

postmarketing adverse drug experience periodic reports. Licensed

biological product distribution reports would be based on the

international birth date and data lock-point. The proposal would also

remove Sec. 600.81 and move the regulatory requirements for licensed

biological product distribution reports to Sec. 600.80(c)(3).

K. Multiple Reports

FDA is proposing to amend Sec. 600.80(g) concerning multiple

reports by adding information pertaining to a licensed biological

product for which a licensed manufacturer holds more than one

biological product license. This revision would be consistent with the

requirements in Sec. 314.80(g).

L. Guidelines

FDA is proposing to amend Secs. 314.80(j) and 600.80(j) to indicate

where guidelines for the submission of adverse experience reports may

be obtained. In addition, FDA is adding this information in

Sec. 310.305(g) for the submission of adverse experience reports for

prescription drugs without an approved application. For human drug

products, the guidelines may be obtained from the CDER Executive

Secretariat Staff (HFD-8), Center for Drug Evaluation and Research,

Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855,

and for licensed biological products from the Congressional and

Consumer Affairs Branch (HFM-12), Center for Biologics Evaluation and

Research, Food and Drug Administration, 1401 Rockville Pike, suite

200N, Rockville, MD 20852-1448.

M. Proposed Implementation Scheme

FDA proposes that any final rule that may issue based on this

proposal become effective 30 days after its date of publication in the

Federal Register. All applications for human drug or licensed

biological products approved on or after the effective date of any

final regulation would be subject to the periodic reporting time

periods based on the international birth date. All human drug and

licensed biological product applications approved before the effective

date of any final regulation would use the U.S. approval date as the

international birth date.

III. Request for Comments

Interested persons may, on or before January 25, 1995, submit to

the Dockets Management Branch (address above) written comments

regarding this proposal. Two copies of any comments are to be

submitted, except that individuals may submit one copy. Comments are to

be identified with the docket number found in brackets in the heading

of this document. Received comments may be seen in the office above

between 9 a.m. and 4 p.m., Monday through Friday.

IV. Environmental Impact

The agency has determined under 21 CFR 25.24(a)(8) that this action

is of a type that does not individually or cumulatively have a

significant effect on the human environment. Therefore, neither an

environmental assessment nor an environmental impact statement is

required.

V. Analysis of Impacts

FDA has examined the impacts of the proposed rule under Executive

Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).

Executive Order 12866 directs agencies to assess all costs and benefits

of available regulatory alternatives and, when regulation is necessary,

to select regulatory approaches that maximize net benefits (including

potential economic, environmental, public health and safety, and other

advantages; distributive impacts; and equity). The agency believes that

this proposed rule is consistent with the regulatory philosophy and

principles identified in the Executive Order. In addition, the proposed

rule is not a significant regulatory action as defined by the Executive

Order and so is not subject to review under the Executive Order.

The economic costs imposed on the industry as a result of this

proposed rule are the costs associated with reporting deaths, serious

adverse experiences, or clinical study discontinuations. Reporting

burdens on the industry resulting from FDA regulations are analyzed

under the Paperwork Reduction Act of 1980. Based on an estimated total

of 480,602 annual burden hours, FDA has estimated that the total annual

reporting cost to the industry as a result of this proposed rule would

be $ 24,030,100 (the estimated per hour cost to the industry is $ 50).

In addition, the rule may increase certain nonpaperwork activities. For

example, added costs may result if the formal control groups suggested

in Sec. 312.23(a)(6)(iii)(i) prompts additional clinical trial control

arms, or if the implementation of the followup plan required in

Sec. 312.23(a)(6)(iii)(k) provokes more elaborate monitoring

procedures. At this time, FDA cannot predict the extent of these

actions, but welcomes public comment on issues regarding the scope or

cost of these activities.

The Regulatory Flexibility Act requires agencies to analyze

regulatory options that would minimize any significant impact of a rule

on small entities. The agency certifies that the proposed rule will not

have a significant economic impact on a substantial number of small

entities. Therefore, under the Regulatory Flexibility Act, no further

analysis is required.

VI. Paperwork Reduction Act of 1980

This proposed rule contains information collection requirements

which are subject to review by the Office of Management and Budget

(OMB) under the Paperwork Reduction Act of 1980. The title,

description, and respondents of the information collection requirements

are shown below.

Title: Adverse Experience Reporting Requirements For Human Drug and

Licensed Biological Products.

Description: FDA is proposing to amend its current adverse

experience reporting requirements to replace current Form FDA-1639 with

new FDA Form 3500A; to revise certain definitions and reporting periods

and formats; to require applicants or manufacturers, packers, and

distributors to develop written procedures for monitoring and reporting

adverse experiences; and to make other revisions to provide uniformity

to the reporting regulations. These changes would simplify and

facilitate the reporting of adverse events and product problems under a

single form and help harmonize international adverse event reporting

requirements. In addition, FDA is proposing to amend the sponsor

reporting requirements in part 312.

Description of Respondents: Businesses or other for profit and

small businesses or organizations.

The burden hours for Secs. 310.305 and 314.80 are approved under

OMB information collection number 0910-0230. The burden hours for

Sec. 600.80 have been submitted to OMB for approval and can be found

elsewhere in this issue of the Federal Register. FDA estimates no

change in the burden hours that have already been approved. OMB has

approved use of the new form, under OMB information collection number

0910-0291, through December 1994. The new recordkeeping requirements

under Sec. 310.305(c)(2), 314.80(c)(1)(ii), and 600.80(c)(1)(ii), that

applicants or manufacturers, packers, and distributors maintain records

of unsuccessful attempts to obtain additional followup information on

15-day ``Alert reports,'' would be negligible and would result in no

change in the burden hours that have already been approved.

The new requirements under Secs. 310.305(a), 314.80(b), and

600.80(b), that applicants or manufacturers, packers, and distributors

develop written procedures for the surveillance, receipt, evaluation,

and reporting of adverse experiences, would not impose a new burden

because they codify a practice that is already customary and usual in

the pharmaceutical industry for handling adverse experiences.

The more extensive list of contents for the periodic postmarketing

adverse experience report, in proposed Secs. 314.80(c)(2)(ii) and

600.80(c)(2)(ii), would result in an increased reporting burden on the

industry. As indicated in the accompanying chart, the proposed periodic

reporting requirements would require, on an average, 19 additional

hours for respondents to prepare.

The proposal would also increase the reporting requirements for

sponsors under part 312. As indicated in the accompanying chart, the

proposed amendments to part 312 would result in an increase of 167,900

burden hours on the industry.

Estimated Total Annual Reporting Burden

----------------------------------------------------------------------------------------------------------------

Number of Responses per Total annual Hours per

Section respondents respondent responses response Total hours

----------------------------------------------------------------------------------------------------------------

312.23(a)(3) and (a)(6)......... 1,623 1 1,623 4 6,492

312.33(b)....................... 1,517 2.6 3,944 40 157,760

312.37(a)....................... 152 1 152 16 2,432

312.37(b)....................... 152 1 152 8 1,216

314.80(c)(2).................... 528 30.50 16,106 19 306,014

600.80(c)(2).................... 63 5.58 352 19 6,688

---------------

Total..................... 480,602

----------------------------------------------------------------------------------------------------------------

As required by section 3504(h) of the Paperwork Reduction Act of

1980, FDA has submitted a copy of this proposed rule to OMB for its

review of these information collection requirements. Other

organizations and individuals desiring to submit comments regarding the

burden estimate or any aspects of these information collection

requirements, including suggestions for reducing the burden, should

direct them to FDA's Dockets Management Branch (address above) and to

the Office of Information and Regulatory Affairs, OMB, rm. 3208, New

Executive Office Bldg., Washington, DC 20503, Attn: Desk Officer for

FDA.

VII. References

The following references have been placed on display in the Dockets

Management Branch (address above) and may be seen by interested persons

between 9 a.m. to 4 p.m., Monday through Friday.

1. ``International Reporting of Adverse Drug Reactions,'' Final

Report of the CIOMS Working Group, 1990.

2. ``International Reporting of Periodic Drug Safety Update

Summaries,'' Final Report of the CIOMS Working Group II, 1992.

3. ``Fialuridine: Hepatic and Pancreatic Toxicity,'' FDA Task

Force Report, November 12, 1993.

4. ``Guideline for Postmarketing Reporting of Adverse Drug

Experiences,'' FDA, Center for Drug Evaluation and Research, March

1992.

List of Subjects

21 CFR Part 20

Confidential business information, Courts, Freedom of information,

Government employees.

21 CFR Part 310

Administrative practice and procedure, Drugs, Labeling, Medical

devices, Reporting and recordkeeping requirements.

21 CFR Part 312

Drugs, Exports, Imports, Investigations, Labeling, Medical

research, Reporting and recordkeeping requirements, Safety.

21 CFR Part 314

Administrative practice and procedure, Confidential business

information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 600

Biologics, Reporting and recordkeeping requirements.

Therefore, under the Federal Food, Drug, and Cosmetic Act, the

Public Health Service Act, and under authority delegated to the

Commissioner of Food and Drugs, it is proposed that 21 CFR parts 20,

310, 312, 314, and 600 be amended as follows:

PART 20--PUBLIC INFORMATION

1. The authority citation for 21 CFR part 20 continues to read as

follows:

Authority: Secs. 201-903 of the Federal Food, Drug, and Cosmetic

Act (21 U.S.C. 321-393); secs. 301, 302, 303, 307, 310, 311, 351,

352, 354-360F, 361, 362, 1701-1706, 2101 of the Public Health

Service Act (42 U.S.C. 241, 242, 242a, 242l, 242n, 243, 262, 263,

263b-263n, 264, 265, 300u-300u-5, 300aa-1); 5 U.S.C. 552; 18 U.S.C.

1905.

Sec. 20.112 [Amended]

2. Section 20.112 Voluntary drug experience reports submitted by

physicians and hospitals is amended in paragraph (a) by removing the

words ``Form FDA-1639'' and adding in their place ``FDA Form 3500''.

PART 310--NEW DRUGS

3. The authority citation for 21 CFR part 310 continues to read as

follows:

Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-

516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and

Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,

360b-360f, 360j, 361(a), 371, 374, 375, 379e); secs. 215, 301,

302(a), 351, 354-360F of the Public Health Service Act (42 U.S.C.

216, 241, 242(a), 262, 263b-263n).

4. Section 310.305 is amended by adding a new sentence at the end

of the concluding text of paragraph (a); by revising paragraphs (b),

(c), (d)(3)(ii), and (d)(4); by removing in paragraph (d)(1) the words

``Form FDA-1639 (Adverse Reaction Report)'' and adding in their place

``FDA Form 3500A''; by removing in paragraph (d)(2), the introductory

text of paragraph (d)(3), and paragraph (d)(3)(i) the words ``Form FDA-

1639'' and adding in their place ``FDA Form 3500A''; by removing in

paragraph (f)(1) the words ``paragraph (c)(5)'' and adding in their

place the words ``paragraph (c)(4)''; and by redesignating paragraph

(g) as paragraph (h) and by adding new paragraph (g) to read as

follows:

Sec. 310.305 Records and reports concerning adverse drug experiences

on marketed prescription drugs for human use without approved new drug

applications.

(a) * * * Manufacturers, packers, and distributors shall also

develop written procedures for the surveillance, receipt, evaluation,

and reporting of adverse drug experiences to FDA.

(b) Definitions. The following definitions of terms apply to this

section:

(1) FDA means the Food and Drug Administration.

(2) Adverse drug experience means any adverse event associated with

the use of a drug in humans, whether or not considered drug related,

including the following: An adverse event occurring in the course of

the use of a drug product in professional practice; an adverse event

occurring from drug overdose; an adverse event occurring from drug

withdrawal; and any failure of expected pharmacological action.

(3) Disability means a substantial disruption of a person's ability

to carry out normal life functions.

(4) Increased frequency means an increase in the rate of occurrence

of a particular adverse drug experience, e.g., an increased number of

reports of particular adverse drug experience after appropriate

adjustment for drug exposure.

(5) Life-threatening means that the patient was, in the view of the

initial reporter, at immediate risk of death from the adverse drug

experience as it occurred. It does not include an adverse drug

experience that, had it occurred in a more serious form, might have

caused death. For example, product-induced hepatitis that resolved

without evidence of hepatic failure would not be considered life-

threatening even though hepatitis of a more severe nature can be fatal.

Similarly, an allergic reaction resulting in angioedema of the face

would not be life-threatening, although angioedema of the larynx,

allergic bronchospasm, or anaphylaxis can be fatal.

(6) Serious means an adverse drug experience occurring at any dose

that is fatal or life-threatening, results in persistent or significant

disability/incapacity, requires or prolongs inpatient hospitalization,

necessitates medical or surgical intervention to preclude permanent

impairment of a body function or permanent damage to a body structure,

or is a congenital anomaly.

(7) Unexpected means an adverse drug experience that is not listed

in the current labeling for the drug product and includes an event that

may be symptomatically and pathophysiologically related to an event

listed in the labeling, but differs from the event because of greater

severity or specificity. For example, under this definition, hepatic

necrosis would be unexpected (by virtue of greater severity) if the

labeling only referred to elevated hepatitic enzymes or hepatitis.

Similarly, cerebral thromboembolism and cerebral vasculitis would be

unexpected (by virtue of greater specificity) if the labeling only

listed cerebral vascular accidents.

(c) Reporting requirements. Each person identified in paragraph

(c)(1) of this section shall report to FDA adverse drug experience

information as described in this section and shall submit one copy of

each report to the Division of Epidemiology and Surveillance (HFD-730),

Center for Drug Evaluation and Research, Food and Drug Administration,

5600 Fishers Lane, Rockville, MD 20857.

(1) Postmarketing 15-Day ``Alert reports''. (i) Any person whose

name appears on the label of a marketed prescription drug product as

its manufacturer, packer, or distributor shall report to FDA each

adverse drug experience received or otherwise obtained that is both

serious and unexpected as soon as possible, but in any case, within 15

calendar days of initial receipt of the information. Each report shall

be accompanied by a copy of the current labeling for the drug product.

(ii) A person identified in paragraph (c)(1)(i) of this section is

not required to submit a 15-day ``Alert report'' for an adverse drug

experience obtained from a postmarketing study (whether or not

conducted under an investigational new drug application) unless the

applicant concludes that there is a reasonable possibility that the

drug caused the adverse experience.

(2) Postmarketing 15-Day ``Alert reports''--followup. Each person

identified in paragraph (c)(1)(i) of this section shall promptly

investigate all serious, unexpected adverse drug experiences that are

the subject of these 15-day postmarketing Alert reports and shall

submit followup reports within 15 calendar days of receipt of new

information or as requested by FDA. If additional information is not

obtainable, records should be maintained of the unsuccessful steps

taken to seek additional information.

(3) Increased frequency report. Each person identified in paragraph

(c)(1)(i) of this section shall review periodically (at least twice

each year) the frequency of reports of adverse drug experiences that

are both serious and expected and reports of therapeutic failure (lack

of effect), received or otherwise obtained, and report any significant

increase in frequency as soon as possible, but in any case within 15

calendar days of determining that a significant increase in frequency

exists. Reports of a significant increase in frequency are required to

be submitted in narrative form (including the time period on which the

increased frequency is based, the method of analysis, and the

interpretation of the results) rather than using FDA Form 3500A.

(4) Submission of reports. In order to avoid unnecessary

duplication in the submission of, and followup to, reports required in

this section, including reports required by paragraph (c)(3) of this

section, a packer's or distributor's obligations may be met by

submission of all reports of serious adverse drug experiences to the

manufacturer of the drug product. If a packer or distributor elects to

submit these adverse drug experience reports to the manufacturer rather

than to FDA, it shall submit each report to the manufacturer within 3

calendar days of its receipt by the packer or distributor, and the

manufacturer shall then comply with the requirements of this section

even if its name does not appear on the label of the drug product.

Under this circumstance, the packer or distributor shall maintain a

record of this action which shall include:

(i) A copy of each drug experience report.

(ii) Date the report was received by the packer or distributor.

(iii) Date the report was submitted to the manufacturer.

(iv) Name and address of the manufacturer.

(5) Each report submitted to FDA under this section shall bear

prominent identification as to its contents, i.e., ``15-day Alert

report,'' ``15-day Alert report--followup,'' or ``Increased frequency

report.''

(6) A person identified in paragraph (c)(1)(i) of this section

should not resubmit to FDA reports forwarded to that person by FDA;

however, all followup information must be submitted to FDA.

(d) * * *

(3) * * *

(ii) The format is agreed to in advance by MedWatch: The FDA

Medical Products Reporting Program.

(4) Ten copies or fewer of FDA Form 3500A and/or a copy of the

instructions for completing the form may be obtained from the Division

of Epidemiology and Surveillance (HFD-730), Center for Drug Evaluation

and Research, Food and Drug Administration, 5600 Fishers Lane,

Rockville, MD 20857. More than 10 copies of the form may be obtained by

writing to the Consolidated Forms and Publications Distribution Center,

Washington Commerce Center, 3222 Hubbard Rd., Landover, MD 20785.

* * * * *

(g) Guideline. FDA has prepared under Sec. 10.90(b) of this chapter

a guideline for the submission of reports of adverse drug experiences

and suggested followup investigation of reports. Copies of this

guideline may be obtained from the CDER Executive Secretariat Staff

(HFD-8), Center for Drug Evaluation and Research, Food and Drug

Administration, 7500 Standish Pl., Rockville, MD 20855.

* * * * *

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

5. The authority citation for 21 CFR part 312 continues to read as

follows:

Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701 of

the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351,

352, 353, 355, 356, 357, 371); sec. 351 of the Public Health Service

Act (42 U.S.C. 262).

6. Section 312.23 is amended by adding new paragraph (a)(3)(v) and

paragraphs (a)(6)(iii)(h) through (a)(6)(iii)(k) to read as follows:

Sec. 312.23 IND content and format.

(a) * * *

(3) * * *

(v) A description of the safety monitoring and evaluation program

developed by the sponsor in order to evaluate safety data reported by

investigators.

* * * * *

(6) * * *

(iii) * * *

(h) A description of any adverse clinical or laboratory outcomes in

the study that are to be reported by the investigators to the sponsor

immediately. This would ordinarily include any death, any life-

threatening event, any serious event that might reflect potential

toxicity, as suggested by preclinical data, laboratory values that

exceed specified limits, or any markedly abnormal laboratory value. The

identified events and abnormal laboratory values are to include those

that focus attention on toxicity that may target the same organs and

body systems as the underlying disease or concomitant medications for

the disease. The events are to be reported to the sponsor even if they

are potentially attributable to the patient's underlying disease or to

other medications the patient may have received. This section of the

protocol shall include instructions for the investigator encountering

such an event, such as reporting requirements, a remeasurement or

challenge procedure, or discontinuation of the study drug.

(i) Sponsors should consider use of a formal control group (for

example, placebo, active, documented historical) in studies that focus

on safety when the underlying disease is likely to produce serious

adverse events that might be confused with drug toxicity.

(j) The sponsor shall estimate the expected incidence of deaths and

serious adverse experiences in the study population that may arise from

the underlying disease or from medications used to treat the underlying

disease. Deaths or serious adverse experiences that exceed these

estimates would create a presumption that the events are associated

with the use of the investigational drug.

(k) The sponsor shall determine and include in each protocol an

appropriate followup period and appropriate followup procedures based

on preclinical data, experience with other members of the drug class,

the drug's mechanism of action, and prior human experience. The sponsor

shall include a brief description of the rationale used in selecting

the followup period and procedures. The intensity of the followup may

change with time; e.g., a full evaluation might be scheduled for 2

weeks after the end of drug dosing, with a telephone followup at a

later time. Ordinarily, in Phase 1 and 2 studies, there should be at

least telephone followup for 3 months after drug dosing is completed,

but alternative timeframes and procedures can be proposed by the

sponsor. In some cases, available information may dictate followup

periods longer than 3 months.

* * * * *

7. Section 312.32 is amended in paragraph (a) by revising the

second sentence in the definition for ``Serious adverse experience,''

paragraph (c)(1)(i), the first sentence in paragraph (c)(2), paragraph

(d)(3), and in paragraph (e) by removing the word ``section'' and

replacing it with the word ``part'' to read as follows:

Sec. 312.32 IND safety reports.

(a) * * *

Serious adverse experience * * * A serious adverse drug experience

means an experience occurring at any dose that is fatal or life-

threatening, results in permanent or significant disability/incapacity,

requires or prolongs inpatient hospitalization, necessitates medical or

surgical intervention to preclude permanent impairment of a body

function or permanent damage to a body structure, or is a congenital

anomaly. * * *

* * * * *

(c) IND safety reports--(1) Written reports. (i) The sponsor shall

notify FDA and all participating investigators in a written IND safety

report of any adverse experience associated with use of the drug that

is both serious and unexpected. This includes notification of any death

or other serious adverse experience that exceeds the estimate of the

expected incidence of deaths and serious adverse experiences required

under Sec. 312.23(a)(6)(iii)(j). Such notification shall be made as

soon as possible and in no event later than 15 calendar days after the

sponsor's initial receipt of the information. Each written notification

may be submitted on FDA Form 3500A or in a narrative form and shall

bear prominent identification of its contents, i.e., ``IND Safety

Report.'' Each written notification to FDA shall be transmitted to the

FDA division of the Center for Drug Evaluation and Research or the

Center for Biologics Evaluation and Research that has responsibility

for review of the IND. If FDA determines that insufficient data were

submitted on FDA Form 3500A, the agency may require further narrative

data to be submitted.

* * * * *

(2) Telephone safety reports. The sponsor shall also notify FDA by

telephone, either orally or by facsimile transmission, of any

unexpected fatal or life-threatening experience associated with the use

of the drug no later than 7 calendar days after the sponsor's initial

receipt of the information. * * *

* * * * *

(d) * * *

(3)If the results of a sponsor's investigation show that an adverse

experience not initially determined to be reportable under paragraph

(c) of this section is so reportable, the sponsor shall report such

experience in a written safety report as soon as possible after the

determination is made, but in no event longer than 15 calendar days.

* * * * *

8. Section 312.33 is revised to read as follows:

Sec. 312.33 Annual and semiannual reports.

(a) Annual reports. A sponsor shall within 60 days of the

anniversary date that the IND went into effect, submit a brief report

of the progress of the investigation that includes:

(1) Individual study information. A brief summary of the status of

each study in progress and each study completed during the previous

year. The summary is required to include the following information for

each study:

(i) The title of the study (with any appropriate study identifiers

such as protocol number), its purpose, a brief statement identifying

the patient population, and a statement as to whether the study is

completed.

(ii) The total number of subjects initially planned for inclusion

in the study, the number entered into the study to date, the number

whose participation in the study was completed as planned, and the

number who dropped out of the study for any reason.

(iii) If the study has been completed, or if interim results are

known, a brief description of any available study results.

(2) Summary information. Information obtained during the previous

year's clinical and nonclinical investigations, including:

(i) A narrative or tabular summary showing the most frequent and

most serious adverse experiences by body system.

(ii) A summary of all IND safety reports submitted during the past

year.

(iii) A list of subjects who died during participation in the

investigation, with the cause of death for each subject.

(iv) A list of subjects who dropped out during the course of the

investigation in association with any adverse experience, whether or

not thought to be drug related.

(v) A brief description of what, if anything, was obtained that is

pertinent to an understanding of the drug's actions, including, for

example, information from controlled trials, and information about

bioavailability.

(vi) A list of the preclinical studies (including animal studies)

completed or in progress during the past year and a summary of the

major preclinical findings.

(vii) A summary of any significant manufacturing or microbiological

changes made during the past year.

(3) A description of the general investigational plan for the

coming year to replace that submitted 1 year earlier. The general

investigational plan shall contain the information required under

Sec. 312.23(a)(3)(iv).

(4) If the investigator brochure has been revised, a description of

the revision and a copy of the new brochure.

(5) A description of any significant Phase 1 protocol modifications

made during the previous year and not previously reported to the IND in

a protocol amendment.

(6) A brief summary of significant foreign marketing developments

with the drug during the past year, such as approval of marketing in

any country or withdrawal or suspension from marketing in any country.

(7) If desired by the sponsor, a log of any outstanding business

with respect to the IND for which the sponsor requests or expects a

reply, comment, or meeting.

(b) Semiannual reports. A sponsor shall submit a report of the

progress of the investigation with respect to safety issues for the 6-

month period following the day the IND goes into effect, and for each

6-month period thereafter, until the end of the followup period

specified in the protocol. The report shall be due within 60 days of

the end of the reporting period. The semiannual safety report that is

due during the same period as the annual report required under

paragraph (a) of this section shall be submitted with the annual

report. These semiannual reports shall include:

(1) A summary and analysis of all deaths, all serious adverse

experiences, and all study discontinuations resulting from an adverse

experience that occurred during the study or within the prescribed

followup period, whether the deaths or adverse experiences were

expected or unexpected and whether or not there is thought to be a

possibility that the death or adverse experience or study

discontinuation was caused by the drug. This summary shall include data

not only from studies conducted under the IND, but also data from all

premarketing studies of the drug conducted worldwide, with an analysis

of all unexpected deaths, serious adverse experiences, and study

discontinuations thought to be related to the study drug from foreign

postmarketing clinical trials and from foreign postmarketing

spontaneous or required reporting systems. For purposes of this

section, serious adverse events shall include laboratory changes

identified in the study protocol as reportable events or that result in

discontinuation. The sponsor shall present in the summary both the data

that accumulated during the reporting period and cumulatively. The

sponsor shall also submit an analysis of the data that assumes that the

investigational drug is responsible for the deaths, serious adverse

experiences, and study discontinuations, and refute, as feasible, this

presumption with appropriate data and evaluations. The expected

incidence of deaths and serious adverse experiences in the study

population that may arise from the underlying disease or from

medications used to treat the underlying disease that was estimated in

the protocol should be considered in this evaluation.

(2) All available autopsy reports and terminal medical reports

concerning all deaths reported in this summary, with a discussion of

any inconsistencies between autopsy and medical reports and the cause

of death reported to FDA by the sponsor.

(3) At the request of the sponsor, or on its own initiative, FDA

may modify the requirements of paragraph (b) of this section. A sponsor

requesting such a modification should submit to the division

responsible for review of the IND a written request for modification

and justification for such modification. FDA shall issue a written

response to the sponsor either granting or denying, in whole or in

part, the request for modification.

(Collection of information requirements approved by the Office of

Management and Budget under control number 0910-0014)

9. Section 312.37 is added to read as follows:

Sec. 312.37 Special safety summary and final clinical study report.

(a) Special safety summary. Upon request of FDA, a sponsor shall

prepare and submit special summaries of safety data regarding the

investigational drug. These summaries may include safety data available

to the sponsor from previous studies of the drug and of closely related

drugs identified in consultation with FDA. Examples of types of events

that may be requested to be summarized include, among others, deaths,

serious adverse experiences, study discontinuations for safety reasons,

patients who reach or exceed safety endpoints as defined in the

protocol, and any unusual or extreme changes in study subjects. The

special safety summary shall be submitted within 30 days after a

request by the agency unless the sponsor demonstrates that

extraordinary circumstances warrant a later date and the agency has

agreed to that later date.

(b) Final clinical study report. Upon request by FDA, a sponsor

shall submit a final report on a clinical study. The final report shall

be submitted within 90 calendar days after a request by the agency

unless the sponsor demonstrates that extraordinary circumstances

warrant a later date and the agency has agreed to that later date.

10. Section 312.42 is amended by adding paragraph (b)(1)(v) to read

as follows:

Sec. 312.42 Clinical holds and requests for modification.

* * * * *

(b) * * *

(1) * * *

(v) The sponsor has failed to submit a special safety summary or

final clinical study report, as required by Sec. 312.37, for the drug

that is the subject of the investigation. This provision applies to

special safety summaries and final clinical study reports from other

investigations on the same drug and special safety summaries and final

clinical study reports requested by FDA for investigations on closely

related drugs conducted by the sponsor.

* * * * *

11. Section 312.44 is amended by revising paragraph (b)(1)(viii) to

read as follows:

Sec. 312.44 Termination.

* * * * *

(b) * * *

(1) * * *

(viii) The sponsor fails to submit an accurate and timely annual or

semiannual safety report of the investigations in accordance with

Sec. 312.33.

* * * * *

12. Section 312.56 is amended by revising paragraph (c) to read as

follows:

Sec. 312.56 Review of ongoing investigations.

* * * * *

(c) Before the initiation of clinical studies, the sponsor shall

develop a safety monitoring and evaluation program to evaluate safety

data reported by the investigator(s). The sponsor shall review and

evaluate the evidence relating to the safety and effectiveness of the

drug as it is obtained from the investigator(s). The sponsor shall make

such reports to FDA regarding information relevant to the safety of the

drug as required under Secs. 312.32 and 312.37. The sponsor shall make

annual and semiannual safety reports in accordance with Sec. 312.33.

* * * * *

13. Section 312.64 is amended by adding two sentences at the end of

paragraph (b) to read as follows:

Sec. 312.64 Investigator reports.

* * * * *

(b) * * * An investigator shall report to the sponsor all adverse

clinical and laboratory outcomes that are required to be reported under

the protocol for the study. These reports shall be made within the time

period specified within the protocol.

* * * * *

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN

ANTIBIOTIC DRUG

14. The authority citation for 21 CFR part 314 continues to read as

follows:

Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701,

704, 721 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321,

331, 351, 352, 353, 355, 356, 357, 371, 374, 379e).

15. Section 314.80 is amended in paragraph (a) by alphabetically

adding definitions for ``Data lock-point,'' ``Disability,''

``International birth date,'' and ``Life-threatening,'' and by revising

the definition of ``Serious;'' by adding two new sentences at the end

of paragraph (b); by revising paragraph (c), the second sentence in

paragraph (d)(1), paragraphs (f)(1), (f)(3)(ii), and (f)(4), and the

last sentence in paragraph (l); by removing in paragraphs (f)(2) and

the introductory text of paragraph (f)(3) the words ``Form FDA-1639''

and adding in their place the words ``FDA Form 3500A''; and by adding a

new sentence at the end of paragraph (j) to read as follows:

Sec. 314.80 Postmarketing reporting of adverse drug experiences.

(a) * * *

* * * * *

Data lock-point means the date designated as the cutoff date for

data to be incorporated into a specific postmarketing adverse drug

experience periodic report. Data available to the applicant after this

date will not be incorporated into the report, unless it represents

important information.

Disability means a substantial disruption of a person's ability to

carry out normal life functions.

* * * * *

International birth date means the date that the first regulatory

authority in the world approved the human drug product for marketing.

Life-threatening means that the patient was, in the view of the

initial reporter, at immediate risk of death from the adverse

experience as it occurred. It does not include an adverse experience

that, had it occurred in a more serious form, might have caused death.

For example, product-induced hepatitis that resolved without evidence

of hepatic failure would not be considered life-threatening even though

hepatitis of a more severe nature can be fatal. Similarly, an allergic

reaction resulting in angioedema of the face would not be life-

threatening, even though angioedema of the larynx, allergic

bronchospasm, or anaphylaxis can be fatal.

Serious means an adverse drug experience occurring at any dose that

is fatal or life-threatening, results in persistent or significant

disability/incapacity, requires or prolongs inpatient hospitalization,

necessitates medical or surgical intervention to preclude permanent

impairment of a body function or permanent damage to a body structure,

or is a congenital anomaly.

* * * * *

(b) * * * Applicants should not resubmit to FDA adverse product

experience reports forwarded to the applicant by FDA; however, they

should submit all followup information to FDA. Applicants shall also

develop written procedures for the surveillance, receipt, evaluation,

and reporting of adverse drug experiences.

(c) Reporting requirements. The applicant shall report to FDA

adverse drug experience information, as described in this section. The

applicant shall submit two copies of each report described in this

section to the Central Document Room, Park Bldg., rm. 2-14, 12420

Parklawn Dr., Rockville, MD 20857. FDA may waive the requirement for

the second copy in appropriate instances.

(1)(i) Postmarketing 15-day ``Alert reports''. The applicant shall

report each adverse drug experience that is both serious and unexpected

as soon as possible but in any case within 15 calendar days of initial

receipt of the information. These reports shall be submitted on FDA

Form 3500A.

(ii) Postmarketing Fifteen-day ``Alert reports''--followup. The

applicant shall promptly investigate all adverse drug experiences that

are the subject of these postmarketing 15-day Alert reports and shall

submit followup reports within 15 calendar days of receipt of new

information or as requested by FDA. If additional information is not

obtainable, records should be maintained of the unsuccessful steps

taken to seek additional information. These postmarketing 15-day Alert

reports and followups to them shall be submitted under separate cover

and may not be included, except for summary or tabular purposes, in a

postmarketing adverse drug experience periodic report.

(iii) Increased frequency report. The applicant shall review

periodically (at least as often as the periodic reporting cycle) the

frequency of reports of adverse drug experiences that are both serious

and expected and reports of therapeutic failure (lack of effect),

regardless of source, and report any significant increase in frequency

as soon as possible but in any case within 15 calendar days of

determining that a significant increase in frequency exists. Upon

written notice, FDA may require that applicants review the frequency of

reports of serious, expected adverse drug experiences at intervals

different than the periodic reporting cycle. Reports of a significant

increase in frequency are required to be submitted in narrative form

(including the time period on which the increased frequency is based,

the method of analysis, and the interpretation of the results), rather

than using FDA Form 3500A. 15-day Alert reports based on increased

frequency are required to be submitted under separate cover and may not

be included, except for summary purposes, in a periodic report.

(iv) Submission of reports. The requirements of paragraphs

(c)(1)(i), (c)(1)(ii), and (c)(1)(iii) of this section, concerning the

submission of postmarketing 15-day Alert reports, shall also apply to

any person (other than the applicant) whose name appears on the label

of an approved drug product as a manufacturer, packer, or distributor.

However, in order to avoid unnecessary duplication in the submission to

FDA of reports required by paragraphs (c)(1)(i), (c)(1)(ii), and

(c)(1)(iii) of this section, obligations of a nonapplicant may be met

by submission of all reports of serious adverse drug experiences to the

applicant. If a nonapplicant elects to submit adverse drug experience

reports to the applicant rather than to FDA, it shall submit each

report to the applicant within 3 calendar days of its receipt by the

nonapplicant, and the applicant shall then comply with the requirements

of this section. Under this circumstance, the nonapplicant shall

maintain a record of this action which shall include:

(A) A copy of the drug experience report.

(B) Date the report was received by the nonapplicant.

(C) Date the report was submitted to the applicant.

(D) Name and address of the applicant.

(v) Report identification. Each report submitted under this

paragraph shall bear prominent identification as to its contents, i.e.,

``15-day Alert report,'' ``15-day Alert report--followup,'' or

``Increased frequency report.''

(2) Periodic adverse drug experience reports. (i) The applicant

shall report every 6 months each adverse drug experience not reported

under paragraphs (c)(1)(i) and (c)(1)(ii) of this section. The periodic

reporting term shall be based upon the international birth date of the

human drug product. The first 6-month anniversary of the international

birth date after the application is approved in the United States is

the data lock-point for the first periodic reporting term. Each

subsequent 6-month anniversary of the international birth date is the

data lock-point for subsequent periodic reporting terms for that

particular product. Periodic reports shall be submitted to FDA within

45 days after the data lock-point. Upon written notice, FDA may require

that the applicant submit reports under this section at times other

than those stated. An applicant who wishes to submit periodic reports

at different intervals must submit to FDA a request for a waiver under

Sec. 314.90. Followup information to adverse drug experiences submitted

initially in a periodic report may be submitted in the next periodic

report. If the applicant does not receive any adverse experience

reports during the reporting period, the applicant shall, in place of a

periodic report, send a copy of the current approved U.S. labeling and

a letter identifying the product, the application number, and the

reporting period, stating that no adverse drug experience reports were

received.

(ii) Reports. Each periodic report shall contain:

(A) Title page, table of contents, and introduction. The

introduction shall be a summary of the periodic report with page

references to detailed data and information.

(B) Applicant's core safety data sheet. The applicant's core safety

data sheet shall be a document prepared by the applicant that contains

all relevant safety information, including adverse drug experiences,

which the applicant believes should be listed for the drug in all

countries where the drug is marketed. It may be used by the applicant

as the reference document by which an adverse drug experience is judged

to be expected or unexpected for purposes of this postmarketing

periodic report. For all other determinations of whether an adverse

drug experience is expected or unexpected, the definition in paragraph

(a) of this section shall apply.

(1) FDA recognizes that the postmarketing periodic report may be

submitted by the applicant to multiple countries and the product may

have different approved labels in the different countries. The use of

the applicant's core safety data sheet as the reference document for

determining whether an adverse drug experience is unexpected or not may

result in some overreporting of unexpected adverse events that actually

are expected by the U.S. approved product label. This is because the

approved label for the United States may have more safety information

included in it than the manufacturer's core safety data sheet. If an

adverse event is not listed in the U.S. label, but is in the

manufacturer's core safety data sheet, this shall be clearly noted in

the ``Overall safety evaluation'' (see paragraph (c)(2) (ii)(H) of this

section). This section also shall highlight clearly any changes and the

reasons for the changes in the applicant's core safety data sheet since

the previous postmarketing periodic report.

(2) An applicant may also use the approved U.S. label as the

reference by which expected and unexpected adverse drug experiences are

determined for the postmarketing periodic report. If an applicant

chooses to use the approved U.S. label for this purpose, it shall

clearly be stated in this section of the report.

(C) The product's marketing status. This section shall contain a

table containing a chronological history of the marketing status of the

product worldwide (all regulatory decisions affecting the product and

all market launches) from the date it was first approved through its

current status. Approvals or applications voluntarily withdrawn for

safety reasons shall be included at a minimum. The product shall be

listed by chemical (or proper name) and brand name(s).

(D) Regulatory actions for safety reasons. This section shall

contain a narrative identifying the reasons for significant regulatory

authority or manufacturer-initiated actions taken anywhere in the

world, or to be taken imminently, for safety reasons during the

reporting period. This includes, for example, application withdrawal or

license suspension or failure to renew, distribution restrictions,

clinical trial suspension, labeling changes due to significant safety

concerns, dosage modifications, or pharmaceutical changes.

(E) Patient exposure. This section shall include the product's

domestic and foreign marketing distribution data during the reporting

period. This shall be used to calculate the extent of patient exposure.

The method used by the manufacturer to estimate patient exposure shall

always be described and shall include the total number of dosage units

of each dosage form and strength or potency (e.g., 100,000/5-milligram

tablets, 50,000/10-milliliter vials).

(F) Individual case histories. This section shall consist of

individual case reports of adverse drug experiences thought possibly

associated with the use of the drug that are:

(1) Serious, unexpected reports from published or unpublished

clinical studies where the applicant has concluded that there is a

reasonable possibility that the drug caused the adverse experience;

(2) Serious, expected or unexpected spontaneous adverse drug

experience reports and nonserious, unexpected spontaneous adverse drug

experience reports (causality always assumed in spontaneous reports)

received directly by the applicant from the initial reporter or

received by the applicant from a drug regulatory authority, both U.S.

or foreign; and

(3) Serious, expected or unexpected, individual published case

histories and nonserious, unexpected individual published case

histories.

(4) All of these reports in paragraphs (c)(2)(ii)(F)(1) through

(c)(2)(ii)(F)(3) of this section shall be presented in line listing

format with the following 10 columns: country, source, age, gender,

dose, duration of treatment (prior to event), time to onset,

description of reaction (as reported), outcome (e.g., fatal, resolved),

other comments (e.g., manufacturer's report number). This format is

consistent with that suggested by CIOMS. In addition, a tabular summary

of the number of adverse events by body system may be included. This

section shall end with an analysis by the reporter, in narrative form,

of the cases submitted. The applicant shall also attach to the end of

the postmarketing periodic report a completed FDA Form 3500A for all

U.S. spontaneous reports of adverse drug experiences except those

reported under paragraphs (c)(1)(i) and (c)(1)(ii) of this section, or

those sent by FDA to the applicant.

(G) Safety studies. This section shall contain an analysis and full

critical discussion of all toxicological, clinical, and epidemiological

studies containing important safety information.

(H) Overall safety evaluation. This section shall contain a

critical analysis and full discussion of the safety information

provided in the periodic report as it pertains to serious unexpected

reactions, increased frequencies of known toxicity, reactions listed in

the manufacturer's core safety data sheet but not included in the U.S.

label, drug interactions, overdose, drug abuse, experiences during

pregnancy or lactation, chronic treatment, pediatric or geriatric

treatment, and new safety issues. The applicant shall indicate when any

significant information has not been obtained. The evaluation shall

indicate whether the safety profile of the product remains consistent

with cumulative experience to date and with the previous manufacturer's

core safety data sheet. The evaluation shall specify any action

recommended and the reasons for such recommendations.

(I) Other information. This section shall include important

information received after the data lock-point.

(J) FDA Form 3500A. An FDA Form 3500A shall be used for each

spontaneous U.S. adverse drug experience not reported under paragraphs

(c)(1)(i) and (c)(1)(ii) of this section.

(K) Location of adverse experience records. The current addresses

where all adverse experience reports and records are maintained.

(d) * * *

(1) * * * The 15-day reporting requirements in paragraph

(c)(1)(iii) of this section (i.e., a significant increase in frequency

of a serious, expected adverse drug experience, or of a therapeutic

failure) apply only to the reports found in scientific and medical

journals either as case reports or as the result of a formal clinical

trial. * * *

* * * * *

(f) Reporting FDA Form 3500A. (1) Except as provided in paragraphs

(c)(1)(iii) and (f)(3) of this section, the applicant shall complete

FDA Form 3500A for each report of an adverse drug experience.

* * * * *

(3) * * *

(ii) The format is agreed to in advance by MedWatch: The FDA

Medical Products Reporting Program.

(4) Ten copies or fewer of FDA Form 3500A and/or a copy of the

instructions for completing the form may be obtained from the Division

of Epidemiology and Surveillance (HFD-730), Center for Drug Evaluation

and Research, Food and Drug Administration, 5600 Fishers Lane,

Rockville, MD 20857. More than 10 copies of the form may be obtained by

writing to the Consolidated Forms and Publications Distribution Center,

Washington Commerce Center, 3222 Hubbard Rd., Landover, MD 20785.

* * * * *

(j) * * * Copies of this guideline may be obtained from the CDER

Executive Secretariat Staff (HFD-8), Center for Drug Evaluation and

Research, Food and Drug Administration, 7500 Standish Pl., Rockville,

MD 20857.

* * * * *

(l) * * * For purposes of this provision, the term ``applicant''

also includes any person reporting under paragraph (c)(1)(iv) of this

section.

* * * * *

PART 600--BIOLOGICAL PRODUCTS: GENERAL

16. The authority citation for 21 CFR part 600 continues to read as

follows:

Authority: Secs. 201, 501, 502, 503, 505, 510, 519, 701, 704 of

the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352,

353, 355, 360, 360i, 371, 374); secs. 215, 351, 352, 353, 361 of the

Public Health Service Act (42 U.S.C. 216, 262, 263, 263a, 264).

17. Section 600.80 as added in a final rule published elsewhere in

this issue of the Federal Register is amended in paragraph (a) by

alphabetically adding definitions for ``Data lock-point,''

``Disability,'' ``International birth date,'' and ``Life-threatening;''

by revising the definition of ``Serious;'' by adding two new sentences

at the end of paragraph (b); by revising paragraph (c), the third

sentence in paragraph (d)(1), paragraph (g), and the last sentence in

paragraph (m); and by adding a new sentence at the end of paragraph (j)

to read as follows:

Sec. 600.80 Postmarketing reporting of adverse experiences.

(a) * * *

* * * * *

Data lock-point means the date designated as the cutoff date for

data to be incorporated into a specific postmarketing adverse

experience periodic report. Data available to the licensed manufacturer

after this date will not be incorporated into the report, unless it

represents important information.

Disability means a substantial disruption of a person's ability to

carry out normal life functions.

* * * * *

International birth date means the date that the first regulatory

authority in the world approved the biological drug product for

marketing.

Life-threatening means that the patient was, in the view of the

initial reporter, at immediate risk of death from the adverse

experience as it occurred. It does not include an adverse experience

that, had it occurred in a more serious form, might have caused death.

For example, product-induced hepatitis that resolved without evidence

of hepatic failure would not be considered life-threatening even though

hepatitis of a more severe nature can be fatal. Similarly, an allergic

reaction resulting in angioedema of the face would not be life-

threatening, even though angioedema of the larynx, allergic

bronchospasm, or anaphylaxis can be fatal.

Serious means an adverse drug experience occurring at any dose that

is fatal or life-threatening, results in persistent or significant

disability/incapacity, requires or prolongs inpatient hospitalization,

necessitates medical or surgical intervention to preclude permanent

impairment of a body function or permanent damage to a body structure,

or is a congenital anomaly.

* * * * *

(b) * * * Licensed manufacturers should not resubmit to FDA adverse

product experience reports forwarded to the licensed manufacturer by

FDA; however, they should submit all followup information to FDA.

Licensed manufacturers shall also develop written procedures for the

surveillance, receipt, evaluation, and reporting of adverse

experiences.

(c) Reporting requirements. The licensed manufacturer shall report

to FDA adverse experience information, as described in this section.

The licensed manufacturer shall submit two copies of each report

described in this section for nonvaccine biological products to the

Center for Biologics Evaluation and Research (HFM-210), Food and Drug

Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-

1448. Submit all vaccine adverse experience reports to: Vaccine Adverse

Event Reporting System (VAERS), P.O. Box 1100, Rockville, MD 20849-

1100. FDA may waive the requirement for the second copy in appropriate

instances.

(1)(i) Postmarketing 15-day ``Alert reports''. The licensed

manufacturer shall report each adverse experience that is both serious

and unexpected as soon as possible, but in any case within 15 calendar

days of initial receipt of the information. These reports shall be

submitted for nonvaccine biological products on FDA Form 3500A, and,

for vaccines, on a VAERS form.

(ii) Postmarketing 15-day ``Alert reports''--followup. The licensed

manufacturer shall promptly investigate all adverse experiences that

are the subject of these postmarketing 15-day Alert reports and shall

submit followup reports within 15 calendar days of receipt of new

information or as requested by FDA. If additional information is not

obtainable, records should be maintained of the unsuccessful steps

taken to seek additional information. These postmarketing 15-day Alert

reports and followups to them shall be submitted under separate cover

and may not be included, except for summary or tabular purposes, in a

postmarketing adverse experience periodic report.

(iii) Increased frequency report. The licensed manufacturer shall

review periodically (at least as often as the periodic reporting cycle)

the frequency of reports of adverse biological product experiences that

are both serious and expected and reports of therapeutic failure (lack

of effect), regardless of source, and report any significant increase

in frequency as soon as possible but in any case within 15 calendar

days of determining that a significant increase in frequency exists.

Upon written notice, FDA may require that licensed manufacturers review

the frequency of reports of serious, expected adverse biological

experiences at intervals different than the periodic reporting cycle.

Reports of a significant increase in frequency are required to be

submitted in narrative form (including the time period on which the

increased frequency is based, the method of analysis, and the

interpretation of the results), rather than using the form designated

by FDA. 15-day Alert reports based on increased frequency are required

to be submitted under separate cover and may not be included, except

for summary purposes, in a periodic report.

(iv) Submission of reports. The requirements of paragraphs

(c)(1)(i), (c)(1)(ii), and (c)(i)(iii) of this section, concerning the

submission of postmarketing 15-day Alert reports, shall also apply to

any person (other than the licensed manufacturer of the final product)

whose name appears on the label of a licensed biological product as a

manufacturer, packer, distributor, shared manufacturer, joint

manufacturer, or any other participant involved in divided

manufacturing. However, in order to avoid unnecessary duplication in

the submission to FDA of reports required by paragraphs (c)(1)(i),

(c)(1)(ii), and (c)(1)(iii) of this section, obligations of a

manufacturer other than the licensed manufacturer, including a licensed

manufacturer of the product other than in its final form, may be met by

submission of all reports of serious adverse experiences to the

licensed manufacturer of the final product. If a manufacturer, other

than the licensed manufacturer, elects to submit reports to the

licensed manufacturer rather than to FDA, it shall submit each report

to the licensed manufacturer within 3 calendar days of its receipt, and

the licensed manufacturer shall then comply with the requirements of

this section. Under this circumstance, the manufacturer shall maintain

a record of this action which shall include:

(A) A copy of all adverse biological product experience reports

submitted to the licensed manufacturer.

(B) Date the report was received by the manufacturer other than the

licensed manufacturer.

(C) Date the report was submitted to the licensed manufacturer.

(D) Name and address of the licensed manufacturer.

(v) Report identification. Each report submitted under this

paragraph shall bear prominent identification as to its contents, i.e.,

``15-day Alert report,'' ``15-day Alert report--followup,'' or

``Increased frequency report.''

(2)(i) Periodic adverse experience reports. The licensed

manufacturer shall report every 6 months each adverse experience not

reported under paragraphs (c)(1)(i) and (c)(1)(ii) of this section. The

periodic reporting term shall be based upon the international birth

date of the biological product. The first 6-month anniversary of the

international birth date after the application is approved in the

United States is the data lock- point for the first periodic reporting

term. Each subsequent 6-month anniversary of the international birth

date is the data lock-point for subsequent periodic reporting terms for

that particular product. Periodic reports shall be submitted to FDA

within 45 days after the data lock-point. Upon written notice, FDA may

require that the licensed manufacturer submit reports under this

section at times other than those stated. A licensed manufacturer who

wishes to submit periodic reports at different intervals must submit to

FDA a request for a waiver under Sec. 600.90. Followup information to

adverse experiences submitted in a periodic report may be submitted in

the next periodic report. If the licensed manufacturer does not receive

any adverse experience reports during the reporting period, the

licensed manufacturer shall, in place of a periodic report, send a copy

of the current approved U.S. labeling and a letter identifying the

product, the application number, and the reporting period, stating that

no adverse experience reports were received.

(ii) Reports. Each periodic report shall contain:

(A) Title page, table of contents, and introduction. The

introduction shall be a summary of the periodic report with page

references to detailed data and information.

(B) Licensed manufacturer's core safety data sheet. The licensed

manufacturer's core safety data sheet shall be a document prepared by

the licensed manufacturer that contains all relevant safety

information, including adverse experiences, which the licensed

manufacturer believes should be listed for the licensed biological

product in all countries where the licensed biological product is

marketed. It may be used by the licensed manufacturer as the reference

document by which an adverse experience is judged to be expected or

unexpected for purposes of this postmarketing periodic report. For all

other determinations of whether an adverse experience is expected or

unexpected, the definition in paragraph (a) of this section shall

apply.

(1) FDA recognizes that the postmarketing periodic report may be

submitted by the licensed manufacturer to multiple countries and the

product may have different approved labels in the different countries.

The use of the licensed manufacturer's core safety data sheet as the

reference document for determining whether an adverse drug experience

is unexpected or not may result in some overreporting of unexpected

adverse events that actually are expected by the U.S. approved product

label. This is because the approved label for the United States may

have more safety information included in it than the licensed

manufacturer's core safety data sheet. If an adverse event is not

listed in the U.S. label, but is in the licensed manufacturer's core

safety data sheet, this shall be clearly noted in the ``Overall safety

evaluation'' (see paragraph (c)(2)(ii)(H) of this section). This

section also shall highlight clearly any changes and the reasons for

the changes in the licensed manufacturer's core safety data sheet since

the previous postmarketing periodic report.

(2) A licensed manufacturer may also use the approved U.S. label as

the reference by which expected and unexpected adverse experiences are

determined for the postmarketing periodic report. If a licensed

manufacturer chooses to use the approved U.S. label for this purpose,

it shall clearly be stated in this section of the report.

(C) The product's marketing status. This section shall contain a

table containing a chronological history of the marketing status of the

product worldwide (all regulatory decisions affecting the product and

all market launches) from the date it was first approved through its

current status. Approvals or applications voluntarily withdrawn for

safety reasons shall be included at a minimum. The product shall be

listed by chemical (or proper name) and brand name(s).

(D) Regulatory actions for safety reasons. This section shall

contain a narrative identifying the reasons for significant regulatory

authority or manufacturer-initiated actions taken anywhere in the

world, or to be taken imminently, for safety reasons during the

reporting period. This includes, for example, licensed application

withdrawal or license suspension or failure to renew, distribution

restrictions, clinical trial suspension, labeling changes due to

significant safety concerns, dosage modifications, or pharmaceutical

changes.

(E) Patient exposure. This section shall include the product's

domestic and foreign marketing distribution data during the reporting

period. This shall be used to calculate the extent of patient exposure.

The method used by the licensed manufacturer to estimate patient

exposure shall always be described and shall include the total number

of dosage units of each dosage form and strength or potency (e.g.,

100,000/5-milligram tablets, 50,000/10-milliliter vials).

(F) Individual case histories. This section shall consist of

individual case reports of adverse experiences thought possibly

associated with the use of the licensed biological product that are:

(1) Serious, unexpected reports from published or unpublished

clinical studies where the licensed manufacturer has concluded that

there is a reasonable possibility that the licensed biological product

caused the adverse experience;

(2) Serious, expected or unexpected spontaneous adverse experience

reports and nonserious, unexpected spontaneous adverse experience

reports (causality always assumed in spontaneous reports) received

directly by the licensed manufacturer from the initial reporter or

received by the licensed manufacturer from a drug regulatory authority,

both U.S. or foreign; and

(3) Serious, expected or unexpected, individual published case

histories and nonserious, unexpected individual published case

histories.

(4) All of these reports under paragraphs (c)(2)(ii)(F)(1) through

(c)(2)(ii)(F)(3) of this section shall be presented in line listing

format with the following 10 columns: country, source, age, gender,

dose, duration of treatment (prior to event), time to onset,

description of reaction (as reported), outcome (e.g., fatal, resolved),

other comments (e.g., manufacturer's report number). This format is

consistent with that suggested by CIOMS. In addition, a tabular summary

of the number of adverse events by body system may be included. This

section shall end with an analysis by the reporter, in narrative form,

of the cases submitted. The licensed manufacturer shall also attach to

the end of the postmarketing periodic report a completed FDA Form 3500A

or VAERS form for all U.S. spontaneous reports of adverse experiences

except those reported under paragraphs (c)(1)(i) and (c)(1)(ii) of this

section, or those sent by FDA to the licensed manufacturer.

(G) Safety studies. This section shall contain an analysis and full

critical discussion of all toxicological, clinical, and epidemiological

studies containing important safety information.

(H) Overall safety evaluation. This section shall contain a

critical analysis and full discussion of the safety information

provided in the periodic report as it pertains to serious unexpected

reactions, increased frequencies of known toxicity, reactions listed in

the manufacturer's core safety data sheet but not included in the U.S.

label, licensed biological product interactions, overdose, licensed

biological product abuse, experiences during pregnancy or lactation,

chronic treatment, pediatric or geriatric treatment, and new safety

issues. The licensed manufacturer shall indicate when any significant

information has not been obtained. The evaluation shall indicate

whether the safety profile of the product remains consistent with

cumulative experience to date and with the previous licensed

manufacturer's core safety data sheet. The evaluation shall specify any

action recommended and the reasons for such recommendations.

(I) Other information. This section shall include important

information received after the data lock-point.

(J) FDA Form 3500A or VAERS Form. An FDA Form 3500A or VAERS form

(for vaccines)shall be used for each spontaneous U.S. adverse

experience not reported under paragraphs (c)(1)(i) and (c)(1)(ii) of

this section.

(K) Location of adverse experience records. The current addresses

where all adverse experience reports and records are maintained.

(3) Distribution reports. The licensed manufacturer shall submit

information about the quantity of the product distributed under the

product license, including the quantity distributed to distributors.

The interval between distribution reports shall be 6 months. The

reporting term shall be based upon the international birth date of the

biological product. The first 6-month anniversary of the international

birth date after the application is approved in the United States is

the data lock-point for the first reporting term. Each subsequent 6-

month anniversary of the international birth date is the data lock-

point for subsequent reporting terms for that particular product.

Distribution reports shall be submitted to FDA within 45 calendar days

after the data lock-point. Upon written notice, FDA may require that

the licensed manufacturer submit distribution reports under this

section at times other than every 6 months. The distribution report

shall consist of the bulk lot number (from which the final container

was filled), the fill lot numbers for the total number of dosage units

of each strength or potency distributed (e.g., 50,000/10-milliliter

vials), the label lot number (if different from fill lot number),

labeled date of expiration, number of doses in fill lot/label lot, date

of release of fill lot/label lot released for distribution at that

time. If any significant amount of a fill lot/label lot is returned,

include this information. Disclosure of financial or pricing data is

not required. As needed, FDA may require submission of more detailed

product distribution information. Upon written notice, FDA may require

that the licensed manufacturer submit reports under this section at

times other than those stated. A licensed manufacturer that wishes to

submit reports at times other than those stated should submit a request

for a waiver under Sec. 600.90.

(d) * * *

(1) * * * The 15-day reporting requirements in paragraph

(c)(1)(iii) of this section (i.e., a significant increase in frequency

of a serious, expected adverse experience or of a therapeutic failure)

apply only to reports found in scientific and medical journals either

as the results of formal clinical trial, or from epidemiologic studies

or analyses of experience in a monitored series of patients. * * *

* * * * *

(g) Multiple reports. A licensed manufacturer should not include in

reports under this section any adverse experience that occurred in

clinical trials if they were previously submitted as part of the

license application. If a report applies to a licensed biological

product for which a licensed manufacturer holds more than one

biological product license, the licensed manufacturer should submit the

report for the license that was first approved. If a report refers to

more than one biological product marketed by a licensed manufacturer,

the licensed manufacturer should submit the report to the license for

the product listed first in the report.

* * * * *

(j) * * * Copies of this guideline may be obtained from the

Congressional and Consumer Affairs Branch (HFM-12), Center for

Biologics Evaluation and Research, Food and Drug Administration, 1401

Rockville Pike, Rockville, MD 20852-1448.

* * * * *

(m) * * * For purposes of this provision, this paragraph also

includes any person reporting under paragraph (c)(1)(iv) of this

section.

Sec. 600.81 [Removed]

18. Section 600.81 Distribution reports (as added in a final rule

published elsewhere in this issue of the Federal Register) is removed.

Dated: October 13, 1994.

William K. Hubbard,

Interim Deputy Commissioner for Policy.

[FR Doc. 94-26483 Filed 10-26-94; 8:45 am]

BILLING CODE 4160-01-F